Treatment of neuropathic pain with 6H-pyrrolo[3,4-d]pyridazine compounds

ABSTRACT

6H-pyrrolo[3,4-d]pyridazine compounds and methods of their use of as ligands of voltage gated calcium channels (VGCC), useful in the treatment of neuropathic pain, and psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson&#39;s disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal and other.

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US03/21493, filed Jul8, 2003, which claims priority from U.S. Ser. No. 60/394,734, filed Jul.11, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed 6H-pyrrolo[3,4-d]pyridazine compoundsand method of their use. In particular, this invention is directed to amethod of use of 6H-pyrrolo[3,4-d]pyridazine compounds in the treatmentof neuropathic pain.

2. Related Background

A major mechanism in many physiological processes, includingneurotransmission in the mammalian nervous system, is the opening andclosing of voltage gated calcium channels (“VGCC”), also known asvoltage sensitive calcium channels (“VSCC”). Such VGCC are formed by theassembly of subunit classes such as alpha 1 and alpha 2. One subunit inthe alpha 2 class is the α₂δ subunit. The activity of the calciumchannel can be modulated by the activities of the component subunits.For example, gabapentin is known to bind with high affinity to the α₂δsubunit. Four isoforms of this α₂δ protein are known and gabapentinbinds with high affinity to 2 of these (α₂δ-1 and α₂δ-2). The relativeimportance of these two activities in accounting for the efficacy andadverse effects of gabapentin is not known. Compounds that displayhigh-affinity binding to the α₂δ subunit of voltage gated calciumchannels have been shown to be efficacious for the treatment of, forexample, neuropathic pain. See, J. Biol. Chem., 271(10):5768-5776(1996)and J. Med. Chem., 41:1838-1845(1998). Nonetheless, if one isoform ismore controlling of the channel modulation, while the other is less,then compounds that are selective to the controlling isoform are likelyto be more efficacious and display fewer side-effects.

Thus, it is desirable to identify other compounds that displayhigh-affinity binding to the α₂δ subunit of voltage gated calciumchannels to provide new medicines in the treatment of neuropathic pain.Further, such compounds can be useful in the treatment of psychiatricand mood disorders such as, for example, schizophrenia, anxiety,depression, bipolar disorders, and panic, as well as in the treatment ofpain, Parkinson's disease, cognitive dysfunction, epilepsy, circadianrhythm and sleep disorders—such as shift-work induced sleep disorder andjet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.

International Patent Publication No. WO 01/88101describes a cell linefor the expression of an α₂δ2 calcium channel subunit.

6-Methyl-6H-pyrrolo[3,4-d]pyridazine is described in MM. J. Duflos etal., Tetrahedron Lett., 3453-3454(1973). 1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo [3,4-d]pyridazine,1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine,5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,and 1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine aredescribed in R. Rips et al., J. Org. Chem., 24:551-554(1959).1,4,5,7-Tetramethyl-6H-pyrrolo[3,4-d]pyridazine,N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide,1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate, and1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine are described inW. L. Mosby, J. Chem. Soc., 3997-4003(1957).5,7-Dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine is described in R.Rips et al., J. Org. Chem., 24:372-374(1959).

5,7-Dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide (alsoknown as5,7-dimethyl-2-(2-oxo-2-phenyl-ethyl)-6H-pyrrolo[3,4-d]pyridazin-2-iumbromide) and2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafloroborate are described in F. Fuentes-Rodriguez et al., J. Chem.Res. Miniprint, 11:2901-2914(1987).5,7-Diphenyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandez etal., J. Chem. Soc., Perkins Trans., 1:899-902(1985), and F. F. Rodriguezet al., J. Chem. Res. Miniprint, 11:3001-3001(1987).5,6,7-Trimethyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandezet al., J. Chem. Soc., Perkin Trans., 1:899-902(1985), F.Fuentes-Rodriguez et al., J. Chem. Res. Miniprint, 11:2901-2914(1987),and R. von Kreher et al., Agnew Chem., 82:958(1970).

1,4-Diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine (also knownas 1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) and5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine(also known as9-methyl-1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) aredescribed in T. Uchida et al., J. Heterocycl. Chem., 15:1303-1307(1978).6-Benzyl-1,4-diphenyl-5-p-tolyl-6, H-pyrrolo[3,4-d]pyridazine6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine,6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline(also known as6,7,10,11-tetraphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene),11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′.5′:3,4]pyrrolo[1,2-a]quinoxaline(also known as11-(4-nitro-phenyl)6,7,10-triphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene),and 6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine are describedin T. Uchida et al., J. Heterocycl. Chem., 15:241-248(1978).

9,12-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline,5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, and1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethylester are described in K. T. Potts et al., J. Org. Chem.,42:1639-1644(1977).7,10-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline, and11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine (alsoknown as 9,12-diphenyl-10,11,13a-triaza-indeno[1,2-l]phenanthrene) aredescribed in K. T. Potts et al., J. Org. Chem., 44:977-979(1979).

1-Oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2,1-c]benzoxazine-1,4(also known as 11-hydroxy-5-oxa-8,9,11a-triaza-benzo[a]fluoren-6-one) isdescribed in Kumashiro et al., Nippon Kagaku Zasshi.,82:1072-1074(1961).10-Methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine,and11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azineare described in M. Noguchi et al., J. Heterocycl. Chem.,22:1049-1053(1985).

1,4-Dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,1-chloro-4ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride,1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,and1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine are described in S.Inel et al., Tetrahedron, 40:3979-3986(1984).

5-Cyano-1,4-dimethylpyridazino[4,5-a]indolizine (also known as1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile),1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile are described inK. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988).5-Cyano-1,4-diphenylpyridazino[4,5-a]indolizine (also known as1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile) is described in K.Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), and K.Matsumoto et al., Heterocycles, 20:1525-1529(1983).6-Methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile are described inK. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), K.Matsumoto et al., Heterocycles, 34:2239-2242(1992), K. Matsumoto et al.,Heterocycles, 20:1525-1529(1983), and K. Matsumoto et al., Can. J.Chem., 71:529-533(1993).5,7-Dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrileare described in K. Matsumoto et al., Heterocycles, 34:2239-2242(1992),and K. Matsumoto et al., Can. J. Chem., 71:529-533(1993).

Dimethyl3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate isdescribed in I. A. Chaudhry et al., Aust. J. Chem.,35:1185-11201(1982).5,6-Dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol,5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride,and 3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4-d]pyridine (alsoknown as 1-methyl-4,7-diphenyl-3-thia-5,6,8a-triaza-cyclopenta[a]indene)are described in W. Losel et al., Chem. Ber., 118:413-427 (1985).1,4-Diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole (also knownas 1,4-diphenyl-5-thia-2,3,9b-triaza-indeno[2,1-a]indene) is describedin N. Abe et al., Bull. Chem. Soc. Japan, 55:200-203(1982).

Nevertheless, there is a need to identify 6H-pyrrolo[3,4-d]pyridazinecompounds that display high-affinity binding—particularly selectivebinding—to the α₂δ subunit of voltage gated calcium channels to providenew medicines in the treatment of neuropathic pain, as well aspsychiatric and mood disorders such as, for example, schizophrenia,anxiety, depression, bipolar disorders, and panic, as well as in thetreatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy,circadian rhythm and sleep disorders—such as shift-work induced sleepdisorder and jet-lag, drug addiction, drug abuse, drug withdrawal andother diseases.

SUMMARY OF THE INVENTION

The present invention is directed to a method of use of6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of neuropathicpain. The present invention is also directed to the use of6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of psychiatricand mood disorders such as, for example, schizophrenia, anxiety,depression, bipolar disorders, and panic, as well as in the treatment ofpain, Parkinson's disease, cognitive dysfunction, epilepsy, circadianrhythm and sleep disorders—such as shift-work induced sleep disorder andjet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.The present invention is also directed to novel6H-pyrrolo[3,4-d]pyridazine compounds that selectively bind to α₂δ-1subunit of Ca channels.

DETAILED DESCRIPTION OF THE INVENTION

A method of treatment of neuropathic pain, and treatment of psychiatricand mood disorders such as, for example, schizophrenia, anxiety,depression, bipolar disorders, and panic, as well as the treatment ofpain, Parkinson's disease, cognitive dysfunction, epilepsy, circadianrhythm and sleep disorders—such as shift-work induced sleep disorder andjet-lag, drug addiction, drug abuse, and drug withdrawal of the presentinvention comprising a step of

administering an effective amount of a compound represented by Formula(I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN; NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl,—C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In one aspect, the method of this invention administers an effectiveamount of a compound represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl optionally substituted with 1-6 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl,—C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In an embodiment of this one aspect, the method of this inventionadministers an effective amount of a compound represented by Formula(I), or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-phenyl optionally substituted with 1-6 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl,—C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In another embodiment of this one aspect, the method of this inventionadministers an effective amount of a compound represented by Formula(I), or a pharmaceutically-acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-phenyl optionally substituted with 1-6 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl or—C₀₋₆alkyl-phenyl, optionally substituted with 1-6 independent halogen,—CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸,—NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸,—SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In another aspect, this invention is directed to a compound representedby Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl,—C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents; provided that the compound is not

6-methyl-6H-pyrrolo[3,4-d]pyridazine,

1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,

5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine,

5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine,

N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)7benzamide,

1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate,

1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine,

5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,

5,7-dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide,

2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafloroborate

5,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,

5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,

1,4diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,

5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,

6-benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo [3,4-d]pyridazine,

6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine.

1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine,

6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,

11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,

6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine,

9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline,

5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,

1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethylester,

7,10-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline,

11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine,

1-oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2.1-c]benzoxazine-1,4,

10-methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine,

11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine,

1,4-dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,

1-chloro-4-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,

1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride,

1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,

1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,

1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,

1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,

5-cyano-1,4-dimethylpyridazino[4,5-a]indolizine,

1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,

6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,

5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine,

6-methyl-1,4diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

5,7-dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,

9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile,

dimethyl3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate,

5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol,

5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride,

3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4-d]pyridine, or

1,4-diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole;

and the compound is not selected from the following table:

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic substituent which is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and naphthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁₋₂alkyl length to the oxyconnecting atom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminal group and is a direct bond whenthe alkyl is a bridging group.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five-memberring containing from 4 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, andtetrazolyl. Examples of heterocycloalkyls include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or nocarbon atoms. However, at least one heteroatom must be present. Thus, asan example, a heteroC₀₋₄alkyl having no carbon atoms but one N atomwould be a —NH— if a bridging group and a —NH₂ if a terminal group.Analogous bridging or terminal groups are clear for an O or Sheteroatom.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines substituted with C₀₋₆alkyl.

The term “carbonyl” unless specifically stated otherwise includes aC₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the alkyl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes the use of all such possible diastereomers as well astheir racemic mixtures, their substantially pure resolved enantiomers,all possible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without-a definitivestereochemistry at certain positions. The present invention includes theuse of all stereoisomers of Formula I and pharmaceutically acceptablesalts thereof. Further, mixtures of stereoisomers as well as isolatedspecific stereoisomers are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound used in the present invention is acidic, its corresponding saltcan be conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound used in the present invention is basic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include, for example, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions used of 2H-pyrrolo[3,4-c]pyridazinecompounds of the present invention comprise a compound represented byFormula I (or pharmaceutically acceptable salts thereof) as an activeingredient, a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients or adjuvants. Such additional therapeuticingredients include, for example, i) opiate agonists or antagonists, ii)calcium channel antagonists, iii) 5HT receptor agonists or antagonistsiv) sodium channel antagonists, v) NMDA receptor agonists orantagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii)non-steroidal anti-inflammatory drugs (“NSAID”), ix) GABA-A receptormodulators, x) dopamine agonists or antagonists, xi) selective serotoninreuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), xii) tricyclicantidepressant drugs, xiv) norepinephrine modulators, xv) L-DOPA, xvi)buspirone, xvii) lithium, xviii) valproate, ixx) neurontin (gabapentin),xx) olanzapine, xxi) nicotinic agonists or antagonists includingnicotine, xxii) muscarinic agonists or antagonists, xxiii) heroinsubstituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiv) disulfiram and acamprosate. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of psychiatric and mood disorderssuch as, for example, schizophrenia, anxiety, depression, panic, bipolardisorders, and circadian disorders, as well as being useful in thetreatment of pain which are responsive to calcium channel modulation, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, schizophrenia, anxiety, depression, and panic may beeffectively treated by the administration of from about 0.01 mg to 75 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. Pain may be effectivelytreated by the administration of from about 0.01 mg to 125 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5 g per patient per day. Further, it is understood thatthe calcium channel modulating compounds of this invention can beadministered at prophylactically effective dosage levels to prevent theabove-recited conditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds used represented by Formula I, orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions used in the present invention can be presented as discreteunits suitable for oral administration such as capsules, cachets ortablets each containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula I, or pharmaceutically acceptable saltsthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions used in this invention may includea pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of Formula I. The compounds of FormulaI, or pharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet Or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions used in the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions used in the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions used in the present invention can be in aform suitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions used in this invention can be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions used in this inventionhave been found to exhibit biological activity as calcium channelligands. Accordingly, another aspect of the invention is the treatmentin mammals of, for example, schizophrenia, anxiety, depression, panic,bipolar disorders, circadian rhythm and sleep disorders, pain,Parkinson's disease, cognitive dysfunction, epilepsy, drug addiction,drug abuse and drug withdrawal—maladies that are amenable toamelioration through modulation of the calcium channel—by theadministration of an effective amount of the compounds of thisinvention. The term “mammals” includes humans, as well as other animalssuch as, for example, dogs, cats, horses, pigs, and cattle. Accordingly,it is understood that the treatment of mammals other than humans is thetreatment of clinical correlating afflictions to those above recitedexamples that are human afflictions.

Further, as described above, the compound used in this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the calcium channel modulating compound used in thisinvention can be advantageously used in combination with i) opiateagonists or antagonists, ii) mGluR5 antagonists, iii) 5HT receptoragonists or antagonists iv) sodium channel antagonists, v) NMDA receptoragonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix)GABA-A receptor modulators, x) dopamine agonists or antagonists, xi)selective serotonin reuptake inhibitors (“SSRI”) and/or selectiveserotonin and norepinephrine reuptake inhibitors (“SSNRI”), xii)tricyclic antidepressant drugs, xiii) norepinephrine modulators, xiv)L-DOPA, xv) buspirone, xvi) lithium, xvii) valproate, xviii) neurontin(gabapentin), xix) olanzapine, xx) nicotinic agonists or antagonistsincluding nicotine, xxi) muscarinic agonists or antagonists, xxii)heroin substituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiii) disulfiram and acamprosate.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise.

Ac acetyl AIBN 2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bnbenzyl CAMP cyclic adenosine-3′,5′-monophosphate DAST(diethylamino)sulfur trifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide Dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃Ntriethylamine GST glutathione transferase HMDS hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅•KHSO₄•K₂SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone) palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. RacemicSAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ Allyl

ALKYL GROUP ABBREVIATIONS Me = Methyl Et = ethyl n-Pr = normal propyli-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen =cyclopentyl c-Hex = cyclohexyl

Assays Demonstrating Biological Activity

The compounds of this invention were tested by the following assays.

Membrane Preparation:

A710 (HEK293 co-expressing α1b, α2δ, β3) cultured in T250 flask wereharvested and washed once with buffer A (20 mM HEPES 10 mM EDTA pH=7.4).The pellet was homogenized in buffer A using a Polytron for 20s. Aftercentrifugation for 10 min, the resulting pellet was washed once with thesame buffer and twice with buffer B (20 mM HEPES 0.1 mM EDTA pH=7.4).The final pellet was resuspended in the same buffer and aliquoted andstored at −70° C. Protein contents was measured by the Biorad D C methodwith bovine serum albumin used as standard.

[³H]-GABApentin Binding:

After thawing, the membranes were washed one time with buffer C (50 mMTRIS pH=7.1) and resuspended in ice cold assay buffer (20 mM HEPESpH=7.4), to have a final protein concentration of 50 μg of protein/well.For the competitive binding experiments, the membranes were incubatedwith 7 nM [³H]-GABApentin for 1 h at rt in the absence or the presenceof at least 11 concentrations of the compounds to be tested. Thenon-specific binding was measured in the presence of 100 μM GABApentin.At the end of the incubation, the suspension was filtered onto 96 wellWhatmann GF/B filter plate (Packard) and washed 3 times with ice-coldassay buffer. The plate was dried and 50 μL of microscint 20 (Packard)was added in each well. The plate was sealed and was counted using aPackard Topcount. The plate was counted (2 min) in normal cpm count modeand transforms in DPM with a constant quench correction.

The compounds of this invention displayed efficacy in the above model byIC₅₀ values of less than 10 μM. The compounds the following table,however, gave IC₅₀ values of more than 10 μM:

Spinal Nerve Ligation Model (Chung Model):

The spinal nerve ligation model of neuropathic pain was used to assessthe effects of test compounds on nerve injury-induced tactile allodynia(S. H. Kim and J. M. Chung, Pain 50:355-363(1992)). Male Sprague Dawleyrats (175-200 g) received unilateral tight ligation of the left L5/L6spinal nerves distal to the dorsal root ganglion using 4-0 silk suture.Behavioral-nociceptive testing occurred 7-14 days following spinal nerveligation by placing the rats in chambers on a wire mesh. Rats weretested for tactile allodynia (decreased hindpaw withdrawal threshold tonon-noxious punctate stimulation) by applying a series of calibrated vonFrey filaments to the plantar aspect of the left hindpaw ipsilateral tothe site of nerve injury. The mean 50% hindpaw withdrawal threshold (g.)was determined using the Dixon “up-down” non-parametric test (Chaplan etal., J. Neurosci. Methods, 53:55-63(1994)). Rats that displayed apre-drug withdrawal threshold >4 g were not considered allodynic andwere excluded from the study. Following determination of pre-drugwithdrawal thresholds, rats received either an i.p. or p.o. injection oftest compound. The effect of the test compound on tactile allodynia wasdetermined over time by measuring hindpaw withdrawal thresholds 30, 60,90, 120 min post-injection. In above model, EXAMPLE 1 produced a 65%effect after i.p. dosing at 30 mg/kg, EXAMPLE 50 produced a 100% effectafter i.p. dosing at 20 mg/kg, EXAMPLE 115 produced a 60% effect afteri.p. dosing at 30 mg/kg i.p.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. When given, yieldsare for illustration only. When given, NMR data is in the form of delta(δ) values for major diagnostic protons, given in parts per million(ppm) relative to tetramethylsilane (TMS) as internal standard,determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.Conventional abbreviations used for signal shape are: s. singlet; d.doublet; t. triplet; m. multiplet; br. broad; etc. In addition, “Ar”signifies an aromatic signal. Chemical symbols have their usualmeanings; the following abbreviations are used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. The substituents are the same as in Formula I exceptwhere defined otherwise.

EXAMPLES 1-47

EXAMPLES 48-84

EXAMPLES 85-370

EXAMPLE 371

EXAMPLE 16-(4-ethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of acetonyl acetone (11.7 mL, 100 mmol) and toluene (750mL) was added p-phenetidine (12.9 mL, 100 mmol) and glacial acetic acid(1 mL). The mixture was heated at reflux overnight. After cooling to rt,the mixture was concentrated in vacuo and purified by columnchromatography on silica gel (15% EtOAc/hexanes) to give2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a pale yellow solid: ¹H NMR(CDCl₃, 500 MHz) δ 7.13-7.10 (m, 2H), 6.97-6.94 (m, 2H), 5.88 (br s,2H), 4.08 (q, 2H), 2.02 (s, 6H), 1.46 (t, 3H); MS (ESI) 216 (M+H)⁺.

Acetic anhydride (8.5 mL, 89 mmol) and hydriodic acid (0.48 mL, 6.3mmol) were added to 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (8.0 g, 37mmol) under nitrogen and the resulting mixture maintained at 100° C.overnight. After cooling to rt, the mixture was diluted with 1N NaOH(200 mL), extracted with EtOAc (2×200 mL), and the combined extractswashed with brine (200 mL), dried (MgSO₄), filtered, concentrated invacuo, and purified by flash chromatography on silica gel (15%EtOAc/hexanes) to give 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrroleas a tan solid: ¹H NM (CDCl₃, 500 MHz) δ 7.08-7.04 (m, 2H), 6.99-6.96(m, 2H), 6.30 (s, 1H), 4.08 (q, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 1.97(s, 3H), 1.45 (t, 3H); MS (ESI) 258 (M+H)⁺.

To a solution of 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200mg, 0.78 mmol) and toluene (4 mL) at 0° C. was added dropwise SnCl₄(0.94 mL, 0.94 mmol, 1.0M solution in CH₂Cl₂) and p-anisoyl chloride(160 mg, 0.94 mmol). The mixture was allowed to warm to rt and heated at50° C. overnight. After cooling to rt, the mixture was diluted with 1NNaOH (15 mL), extracted with EtOAc (2×15 mL), and the combined extractswashed with brine (15 mL), dried (MgSO₄), filtered, concentrated invacuo, and purified by flash chromatography (0-33% EtOAc/hexanes). Theresulting residue was dissolved in EtOH (5 mL) and hydrazine (0.5 mL).The solution was stirred at 50° C. overnight, cooled to rt, andconcentrated in vacuo to give6-(4-ethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.57-7.54 (m, 2H),7.12-7.09 (m, 2H), 7.05-7.03 (m, 2H), 6.99-6.97 (m, 2H), 4.11 (q, 2H),3.85 (s, 3H), 2.90 (s, 3H), 2.49 (s, 3H), 1.94 (s, 3H), 1.47 (t, 3H); MS(ESI) 388 (M+H)⁺.

EXAMPLE 21,4-diethyl-5,7-dimethyl-6-(4-ethoxyphenyl)-6H-pyrrolo[3,4-d]pyridazine

To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl₄ (4.7mL, 4.7 mmol, 1.0M solution in CH₂Cl₂) and propionyl chloride (0.40 mL,4.7 mmol). The mixture was warmed to rt and then heated at 50° C.overnight. After cooling to rt, the mixture was quenched with 1N NaOH(50 mL), extracted with EtOAc (2×50 mL), the combined extracts washedwith brine (50 mL), dried (MgSO₄), filtered, concentrated in vacuo, andpurified by flash chromatography on silica gel (0-25% EtOAc/hexanes).The resulting residue was dissolved in EtOH (10 mL) and hydrazine (0.1mL). The resulting solution was maintained at 50° C. overnight, cooledto rt, and concentrated in vacuo to give1,4-diethyl-5,7-dimethyl-6-(4-ethoxyphenyl)-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.10 (m, 2H),7.06-7.03 (m, 2H), 4.12 (q, 2H), 3.11 (q, 4H), 2.40 (s, 6H), 1.48 (t,3H), 1.39 (t, 6H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 36-(4-ethoxyphenyl)-1-ethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) andpropionyl chloride (0.08 mL, 0.94 mmol) reacted to give6-(4-ethoxyphenyl)-1-ethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.11 (m, 2H),7.08-7.05 (m, 2H), 4.13 (q, 2H), 3.15 (q, 2H), 2.85 (s, 3H), 2.45 (s,3H), 2.42 (s, 3H), 1.49 (t, 3H), 1.40 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 46-(4-ethoxyphenyl)-1-phenyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl₄ (4.7mL, 4.7 mmol, 1.0M solution in CH₂Cl₂) and benzoyl chloride (0.54 mL,4.7 mmol). The mixture was warmed to rt and heated at 50° C. overnight.After cooling to rt, the mixture was diluted with 1N NaOH (50 mL),extracted with EtOAc (2×50 mL), the combined extracts washed with brine(50 mL), dried MgSO₄), filtered, concentrated in vacuo, and purified byflash chromatography on silica gel (0-25% EtOAc/hexanes) to give3-benzoyl-2,5-dimethyl-1-(4ethoxyphenyl)pyrrole as a tan solid: ¹H NMR(CDCl₃, 500 MHz) δ 7.84-7.82 (m, 2H), 7.52-7.43 (m, 3H), 7.14-7.12 (m,2H), 7.01-6.98 (m, 2H), 6.18 (s, 1H), 4.10 (q, 2H), 2.33 (s, 3H), 1.98(s, 3H), 1.47 (t, 3H). MS (ESI) 320 (M+H)⁺.

To a solution of 3-benzoyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (201mg, 0.63 mmol) and toluene (5 mL) at 0° C. was added dropwise SnCl₄(0.76 mL, 0.76 mmol, 1.0M solution in CH₂Cl₂) and acetyl chloride (0.06mL, 0.76 mmol). The mixture was warmed to rt overnight, quenched with 1NNaOH (10 mL), extracted with EtOAc (2×20 mL), the combined extractswashed with brine (50 mL), dried (MgSO₄), filtered, concentrated invacuo, and purified by flash chromatography on silica gel (0-33%EtOAc/hexanes). The resulting residue was dissolved in EtOH (5 mL) andhydrazine (0.1 mL). The solution was stirred at rt overnight andconcentrated in vacuo to give6-(4-ethoxyphenyl)-1-phenyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.59 (m, 2H), 7.47-7.44(m, 3H), 7.12-7.09 (m, 2H), 7.05-7.02 (m, 2H), 4.11 (q, 2H), 2.89 (s,3H), 2.49 (s, 3H), 1.87 (s, 3H), 1.47 (t, 3H). MS (ESI) 358 (M+H)⁺.

EXAMPLE 56-(4-ethoxyphenyl)-1-(3-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) andm-anisoyl chloride (0.13 mL, 0.94 mmol) reacted to give6-(4-ethoxyphenyl)-1-(3-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.33 (m, 1H),7.18-7.14 (m, 2H), 7.13-7.08 (m, 2H), 7.07-7.02 (m, 2H), 7.01-6.97 (m,1H), 4.11 (q, 2H), 3.84 (s, 3H), 2.96 (s, 3H), 2.51 (s, 3H), 1.92 (s,3H), 1.47 (t, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 66-(4-ethoxyphenyl)-1-(3-benzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) andphenacetyl chloride (0.16 mL, 0.94 mmol) reacted to give6-(4-ethoxyphenyl)-1-(3-benzyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.33 (m, 1H),7.18-7.14 (m, 3H), 7.13-7.08 (m, 2H), 7.07-7.02 (m, 2H), 7.01-6.97 (m,1H), 4.51 (s, 2H), 4.11 (q, 2H), 3.84 (s, 3H), 2.96 (s, 3H), 2.51 (s,3H), 1.92 (s, 3H), 1.47 (t, 3H); MS (ESI) 372 (M+H)⁺.

EXAMPLE 71-(4chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and4-chlorobenzoyl chloride (0.14 mL, 0.94 mmol) reacted to give1-(4-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.58-7.53 (m, 2H),7.46-7.41 (m, 2H), 7.14-7.08 (m, 2H), 7.07-7.02 (m, 2H), 4.11 (q, 2H),2.94 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H), 1.48 (t, 3H); MS (ESI) 392(M+H)⁺.

EXAMPLE 86-(4-ethoxyphenyl)-1-(2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) ando-anisoyl chloride (0.14 mL, 0.94 mmol) reacted to give6-(4-ethoxyphenyl)-1-(2-methoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.47-7.41 (m, 1H),7.39-7.34 (m, 1H), 7.17-7.12 (m, 1H), 7.10-7.01 (m, 4H), 7.00-6.95 (m,1H), 4.10 (q, 2H), 3.73 (s, 3H), 2.96 (s, 3H), 2.49 (s, 3H), 1.77 (s,3H), 1.47 (t, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 91-(3chlorophenyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and3-chlorobenzoyl chloride (0.12 mL, 0.94 mmol) reacted to give1-(3-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.58 (m, 1H),7.53-7.48 (m, 1H), 7.44-7.37 (m, 2H), 7.14-7.09 (m, 2H), 7.07-7.03 (m,2H), 4.11 (q, 2H), 2.97 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H), 1.47 (t,3H); MS (ESI) 392 (M+H)⁺.

EXAMPLE 101-(2-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and2-chlorobenzoyl chloride (0.12 mL, 0.94 mmol) reacted to give1-(2-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.48-7.43 (m, 2H),7.40-7.34 (m, 2H), 7.17-7.12 (m, 1H), 7.08-6.99 (m, 3H), 4.10 (q, 2H),2.93 (s, 3H), 2.50 (s, 3H), 1.74 (s, 3H), 1.46 (t, 3H); MS (ESI) 392(M+H)⁺.

EXAMPLE 116-(4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) andp-toluoyl chloride (0.13 mL, 1.0 mmol) reacted to give6-(4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.50 (d, 2H), 7.26 (d, 2H),7.12-7.10 (m, 2H), 7.05-7.03 (m, 2H), 4.11 (q, 2H), 2.93 (s, 3H), 2.50(s, 3H), 2.41 (s, 3H), 1.91 (s, 3H), 1.47 (t, 3H); MS ESI) 372 (M+H)⁺.

EXAMPLE 126-(4-ethoxyphenyl)-1-(4-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and4-ethylbenzoyl chloride (0.15 mL, 1.0 mmol) reacted to give6-(4-ethoxyphenyl)-1-(4-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.54-7.51 (m, 2H),7.29-7.25 (m, 2H), 7.12-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.11 (q, 2H),2.93 (s, 3H), 2.71 (q, 2H), 2.50 (s, 3H), 1.91 (s, 3H), 1.47 (t, 3H),1.26 (t, 3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 131-(1-cyclopentethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and3-cyclopentylpropionyl chloride (0.18 mL, 1.2 mmol) reacted to give1-(1-cyclopentylethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.07-7.03(m, 2H), 4.11 (q, 2H), 3.09 (dd, 2H), 2.77 (s, 3H), 2.42 (s, 3H), 2.40(s, 3H), 1.98-1.89 (m, 1H), 1.87-1.77 (m, 4H), 1.63-1.56 (m, 2H),1.55-1.47 (m, 2H), 1.48 (t, 3H), 1.20-1.15 (m, 2H); MS (ESI) 378 (M+H)⁺.

EXAMPLE 141-(4-ethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and4-ethoxybenzoyl chloride (185 mg, 1.0 mmol) reacted to give1-(4-ethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.55 (d, 2H), 7.12-7.09 (m,2H), 7.05-7.03 (m, 2H), 6.97 (d, 2H), 4.14-4.06 (m, 4H), 2.93 (s, 3H),2.50 (s, 3H), 1.94 (s, 3H), 1.47 (t, 3H), 1.43 (t, 3H); MS (ESI) 402(M+H)⁺.

EXAMPLE 151-(cyclopropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andcyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) reacted to give1-(cyclopropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.14-7.10 (m, 2H), 7.07-7.03(m, 2H), 4.12 (q, 2H), 2.76 (s, 3H), 2.52 (s, 3H), 2.42 (s, 3H), 2.38(quintet, 1H), 1.49 (t, 3H), 1.34-1.32 (m, 2H), 0.99-0.96 (m, 2H); MS(ESI) 322 (M+H)⁺.

EXAMPLE 166-(4-ethoxyphenyl)-1-(2-methylpropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andisovaleryl chloride (0.15 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-(2-methylpropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.09 (m, 2H), 7.06-7.03(m, 2H), 4.12 (q, 2H), 2.94 (d, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.38(s, 3H), 2.18-2.10 (m, 1H), 1.48 (t, 3H), 1.01 (d, 6H); MS (ESI) 338(M+H)⁺.

EXAMPLE 171-(cyclopentyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andcyclopentanecarbonyl chloride (0.15 mL, 1.2 mmol) reacted to give1-(cyclopentyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.09 (m, 2H), 7.06-7.02(m, 2H), 4.12 (q, 2H), 3.67 (quintet, 1H), 2.77 (s, 3H), 2.42 (s, 6H),2.26-2.19 (m, 2H), 2.02-1.93 (m, 2), 1.92-1.84 (m, 2H) 1.70-1.63 (m,2H), 1.48 (t, 3H); MS (ESI) 350 (M+H)⁺.

EXAMPLE 181-(cyclopentylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andcyclopentylacetyl chloride (176 mg, 1.2 mmol) reacted to give1-(cyclopentylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.06-7.02(m, 2H), 4.12 (q, 2H), 3.08 (d, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.40(s, 3H), 2.41-2.32 (m, 1H), 1.79-1.72 (m, 2H), 1.70-1.62 (m, 2H)1.55-1.46 (m, 2H), 1.48 (t, 3H), 1.44-1.37 (m, 2H); MS (ESI) 364 (M+H)⁺.

EXAMPLE 191-(cyclohexyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andcyclohexanecarbonyl chloride (0.16 mL, 1.2 mmol) reacted to give1-(cyclohexyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.08 (m, 2H), 7.06-7.02(m, 2H), 4.12 (q, 2H), 3.14 (tt, 1H), 2.77 (s, 3H), 2.41 (s, 3H), 2.39(s, 3H), 2.04-1.98 (m, 2H), 1.95-1.82 (m, 4H), 1.78-1.72 (m, 1H) 1.48(t, 3H), 1.44-1.34 (m, 3H); MS (ESI) 364 (M+H)⁺.

EXAMPLE 206-(4-ethoxyphenyl)-1-pentyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol)-andhexanoyl chloride (0.17 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-penyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.06-7.03(m, 2H), 4.12 (q, 2H), 3.06 (dd, 2H), 2.77 (s, 3H), 2.42 (s, 3H), 2.39(s, 3H), 1.81-1.75 (m, 2H), 1.50-1.44 (m, 2), 1.48 (t, 3H), 1.42-1.34(m, 2H), 0.89 (t, 3H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 216-(4-ethoxyphenyl)-1-(4-fluorophenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and4-fluorobenzoyl chloride (0.12 mL, 1.0 mmol) reacted to give6-(4-ethoxyphenyl)-1-(4-fluorophenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellowish solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.58 (m, 2H),7.18-7.08 (m, 4H), 7.07-7.03 (m, 2H), 4.11 (q, 2H), 2.95 (s, 3H), 2.51(s, 3H), 1.91 (s, 3H), 1.48 (t, 3H); MS (ESI) 376 (M+H)⁺.

EXAMPLE 226-(4-ethoxyphenyl)-1-(2,2,4-trimethylpentyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and3,5,5-trimethylhexanoyl chloride (0.23 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-(2,2,4-trimethylpentyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid:

¹H NMR (CDCl₃, 500 MHz) δ 7.14-7.08 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q,2H), 2.99 (dd, 1H), 2.92 (dd, 1H), 2.78 (s, 3H), 2.42 (s, 3H), 2.40 (s,3H), 2.15 (quintet, 1H), 1.53 (dd, 1H), 1.49 (t, 3H), 1.21 (dd, 1H),1.02 (d, 3H), 0.82 (s, 9H); MS (ESI) 394 (M+H)⁺.

EXAMPLE 236-(4-ethoxyphenyl)-1-(1-phenylethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andhydrocinnamoyl chloride (0.18 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-(1-phenylethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.31-7.26 (m, 4H), 7.22-7.18(m, 1H), 7.12-7.09 (m, 2H), 7.06-7.04 (m, 2H), 4.12 (q, 2H), 3.38 (dd,2H), 3.15 (dd, 2H), 2.79 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.48 (t,3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 241-(2,2-dimethylpropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) andtert-butylacetyl chloride (0.17 mL, 1.2 mmol) reacted to give1-(2,2-dimethylpropyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.08 (m, 2H), 7.06-7.02(m, 2H), 4.12 (q, 2H), 3.03 (s, 2H), 2.79 (s, 3H), 2.43 (s, 3H), 2.42(s, 3H), 1.48 (t, 3H), 1.06 (s, 9H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 256-(4-ethoxyphenyl)-1-(4-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and4-methoxyphenylacetyl chloride (0.19 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-(4-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.16 (d, 2H), 7.05-6.98 (m,4H), 6.76 (d, 2H), 4.39 (s, 2H), 4.09 (q, 2H), 3.74 (s, 3H), 2.81 (s,3H), 2.41 (s, 3H), 2.19 (s, 3H), 1.46 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 266-(4-ethoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and4-(trifluoromethoxy)benzoyl chloride (0.16 mL, 1.0 mmol) reacted to givethe product which was taken up in hot ether, precipitated with HCl inether, and filtered to give6-(4-ethoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellow solid: ¹H NMR (d₆-DMSO, 500 MHz) δ 7.86 (d, 2H), 7.62 (d,2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.14 (q, 2H), 3.14 (s, 3H), 2.60 (s,3H), 1.94 (s, 3H), 1.38 (t, 3H); MS (ESI) 442 (M+H)⁺.

EXAMPLE 276-(4-ethoxyphenyl)-1-(3-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyrdazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and3-methoxyphenylacetyl chloride (0.19 mL, 1.2 mmol) reacted to give6-(4-ethoxyphenyl)-1-(3-methoxyphenylmethyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.15 (dd, 1H), 7.06-7.03 (m,2H), 7.02-6.98 (m, 2H), 6.83 (d, 1H), 6.80 (s, 1H), 6.71 (d, 1H), 4.43(s, 2H), 4.09 (q, 2H), 3.72 (s, 3H), 2.81 (s, 3H), 2.42 (s, 3H), 2.20(s, 3H), 1.46 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 281-(4-bromophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) andp-bromobenzoyl chloride (220 mg, 1.0 mmol) reacted to give the productwhich was taken up in hot ether, precipitated with HCl in ether, andfiltered to give1-(4-bromophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.83 (d,2H), 7.66 (d, 2H), 7.37 (d, 2H), 7.20 (d, 2H), 4.14 (q, 2H), 3.12 (s,3H), 2.59 (s, 3H), 1.94 (s, 3H), 1.38 (t, 3H); MS (ESI) 437 (M+H)⁺.

EXAMPLE 291-(2,4-dimethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and2,4-dimethoxybenzoyl chloride (201 mg, 1.0 mmol) reacted to give theproduct which was taken up in hot ether, precipitated with HCl in ether,and filtered to give1-(2,4-dimethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.41-7.30(m, 3H), 7.18 (d, 2H), 6.80-6.73 (m, 2H), 4.14 (q, 2H), 3.87 (s, 3H),3.76 (s, 3H), 3.03 (br s, 3H), 2.54 (s, 3H), 1.87 (s, 3H), 1.38 (t, 3H);MS (ESI) 418 (M+H)⁺.

EXAMPLE 301-(4-biphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and4-biphenylcarbonyl chloride (217 mg, 1.0 mmol) reacted to give1-(4-biphenyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.73-7.64 (m, 4H), 7.60 (d,2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.11 (d, 2H), 7.03 (d, 2H), 4.11 (q,2H), 2.87 (s, 3H), 2.49 (s, 3H), 1.95 (s, 3H), 1.47 (t, 3H); MS (ESI)434 (M+H)⁺.

EXAMPLE 314-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid methyl ester

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) andmethyl 5-chloro-5-oxovalerate (0.63 mL, 4.5 mmol) reacted to give5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoicacid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05 (d,2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.65 (s, 3H), 2.75 (t, 2H), 2.41 (s,3H), 2.40 (t, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 2.00 (quintet, 2H), 1.45(t, 3H); MS (ESI) 386 (M+H)⁺.

To a solution of5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoicacid methyl ester (250 mg, 0.65 mmol) in ethanol (1 mL) was added a 1.0Msolution of hydrazine in ethanol (0.72 mL, 0.72 mmol). The solution wasstirred overnight at rt and concentrated in vacuo to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.08(m, 2H), 7.05-7.03 (in, 2H), 4.11 (q, 2H), 3.63 (s, 3H), 3.12 (t, 2H),2.77 (s, 3H), 2.51 (t, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.14 (quintet,2H), 1.47 (t, 3H); MS (ESI) 382 (M+H)⁺.

EXAMPLE 324-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]propionicacid methyl ester

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) andmethyl 4-chloro-4-oxobutyrate (0.56 mL, 4.5 mmol) reacted to give4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]4-oxo-butyricacid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d,2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.67 (s, 3H), 3.03 (t, 211), 2.74 (t,2H), 2.41 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.45 (t, 3H); MS (ESI)372 (M+H)⁺.

To a solution of4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-4-oxo-butyricacid methyl ester (250 mg, 0.67 mmol) in ethanol (1 mL) was added a 1.0Msolution of hydrazine in ethanol (0.74 mL, 0.74 mmol). The solution wasstirred overnight at rt and concentrated in vacuo to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.08(m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 3.70 (s, 3), 3.43 (t, 2H),3.00 (t, 2H), 2.79 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H), 1.48 (t, 3H); MS(ESI) 368 (M+H)⁺.

EXAMPLE 331-(cyclopropyl)-6-(2,4-dimethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone(5.88 mL, 50 mmol) and 2,4-dimethoxyaniline (7.12 mL, 50 mmol) reactedto give 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹HNMR (CDCl₃, 500 MHz) δ 7.08 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 5.90(s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.97 (s, 6H); MS (ESI) 232 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (2.31 g, 10 mmol), aceticanhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give3-acetyl-1-(2,4dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹HNMR (CDCl₃, 500 MHz) δ 7.02 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 6.32(s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 1.93(s, 3H); MS (ESI) 274 (M+H)⁺.

To a solution of 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole(273 mg, 1.0 mmol) in toluene (5 mL) at −78° C. was added3-cyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) followed by dropwiseaddition of a 1.0M solution of tin(IV) chloride in CH₂Cl₂ (1.2 mL, 1.2mmol). The reaction was allowed to warm to room temp overnight. Thesolution was diluted with 0.25M NaOH, extracted with EtOAc, the organiclayer washed with brine, dried over MgSO₄, filtered, concentrated invacuo, and purified by flash chromatography (10-25% EtOAc/hexanes) togive the dione (MS (ESI) 342 (M +H)⁺). The dione was taken up in ethanol(5 mL) and excess hydrazine (0.1 mL) was added. The solution was stirredat 40° C. overnight, poured into water, and filtered to give1-(cyclopropyl)-6-(2,4-dimethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (dd, 1H), 6.66-6.56 (m,2H), 3.90 (s, 3H), 3.75 (s, 3H), 2.75 (s, 3H), 2.47 (s, 3H), 2.39(quintet, 1H), 2.38 (s, 3H), 1.35-1.28 (m, 2H), 0.97 (dd, 2H); MS (ESI)338 (M+H)⁺.

EXAMPLE 346-(2,4-dimethoxyphenyl)-1-(4-methylphenl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 33,3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (273 mg, 1.0 mmol)and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give the productas a clear oil which was taken up in ether, precipitated with HCl inether, and filtered to give6-(2,4-dimethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.58-7.51(m, 2H), 7.45-7.37 (m, 2H), 7.33 (dd, 1H), 6.92 (d, 1H), 6.79 (dd, 1H),3.90 (s, 3H), 3.77 (s, 3H), 3.08 (br s, 3H), 2.50 (br s, 3H), 2.44 (s,3H), 1.90 (s, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 356-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 33,3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (273 mg, 1.0 mmol)and p-anisoyl chloride (0.28 mL, 2.0 mmol) reacted to give the productas a clear oil which was taken up in ether, precipitated with HCl inether, and filtered to give6-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.58-7.51(m, 2H), 7.45-7.37 (m, 2H), 7.33 (dd, 1H), 6.92 (d, 1H), 6.79 (dd, 1H),3.90 (s, 3H), 3.87 (s 3H), 3.77 (s, 3H), 3.08 (br s, 3H), 2.50 (s, 3H),2.00 (s, 3H); MS (ESI) 404 (M+H)⁺.

EXAMPLE 361-(cyclopropyl)-6-(4-ethoxy-2-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone(5.88 mL, 50 mmol) and o-cresol (6.12, 50 mmol) reacted to give1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole as a colorless oil: ¹HNMR (CDCl₃, 500 MHz) δ 7.05 (d, 1H), 6.80 (d, 1H), 6.75 (dd, 1H), 5.96(s, 2H), 5.10 (br s, 1H), 1.96 (s, 6H), 1.92 (s, 3H); MS (ESI) 202(M+H)⁺.

To a solution of 1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole (˜50mmol) in acetonitrile (300 mL) was added potassium carbonate (55 mmol)and an excess of bromoethane (>100 mmol). The reaction mixture wasstirred at 50° C. overnight, cooled to room temperature, and partitionedbetween EtOAc and water. The organic layer was washed with brine, driedover MgSO₄, filtered, concentrated in vacuo, and purified by columnchromatography (15% EtOAc/hexanes) to give2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a colorless oil: ¹HNMR (CDCl₃, 500 MHz) δ 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (dd, 1H), 5.90(s, 2H), 4.07 (q, 2H), 1.92 (s, 6H), 1.90 (s, 3H), 1.45 (t, 3H; MS (ESI)230 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (2.29 g, 10 mmol),acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reactedto give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as atan solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.99 (d, 1H), 6.85 (d, 1H), 6.79(dd, 1H), 6.32 (s, 1H), 4.06 (q, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.89(s, 3H), 1.88 (s, 3H), 1.44 (t, 3H); MS (ESI) 272 (M +H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0mmol) and 3-cyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) reacted togive1-(cyclopropyl)-6-(4-ethoxy-2-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (d, 1H), 6.92 (d, 1H),6.88 (dd, 2H), 4.10 (q, 2H), 2.76 (s, 3H), 2.45 (s, 3H), 2.38 (quintet,1H), 2.35 (s, 3H), 1.83 (s, 3H), 1.47 (t, 3H), 1.39-1.31 (m, 2H), 0.98(dd, 2H); MS (ESI) 336 (M+H)⁺.

EXAMPLE 376-(4-ethoxy-2-methylphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 36,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0mmol) and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give theproduct as a clear oil which was taken up in ether, precipitated withHCl in ether, and filtered to give6-(4-ethoxy-2-methylphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.63-7.59(m, 2H), 7.47-7.39 (m, 2H), 7.24 (d, 1H), 7.13 (d, 1H), 7.03 (dd, 1H),4.12 (q, 2H), 3.09 (br s, 3H), 2.51 (br s, 3H), 2.44 (s, 3H), 1.89 (s,3H), 1.83 (s, 3H), 1.37 (t, 3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 386-(4-ethoxy-2-methylphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 36,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0mmol) and p-anisoyl chloride (0.28 mL, 2.0 mmol) reacted to give theproduct as a clear oil which was taken up in ether, precipitated withHCl in ether, and filtered to give6-(4-ethoxy-2-methylphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.63-7.59(m, 2H), 7.47-7.39 (m, 2H), 7.24 (d, 1H), 7.13 (d, 1H), 7.03 (dd, 1H),4.12 (q, 2H), 3.87 (s, 3H), 3.09 (br s, 3H), 2.51 (br s, 3H), 2.44 (s,3H), 1.89 (s, 3H), 1.37 (t, 3H); MS (ESI) 404 (M+H)⁺.

EXAMPLE 396-(3-chloro-4-ethoxyphenyl)-1-(cyclopropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone(0.83 mL, 7.0 mmol) and 4-amino-2-chlorophenol (1.0 g, 7.0 mmol) reactedto give 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole as a brownsolid: ¹H NMR (CDCl₃, 500 MHz) δ 7.22 (d, 1H), 7.10 (d, 1H), 7.05 (dd,1H), 5.88 (s, 2H), 5.66 (br s, 1H), 2.03 (s, 6H); MS (ESI) 222 (M+H)⁺.

Using the general procedure outlined in EXAMPLE 1,1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole (1.11 g, 5 mmol) and anexcess of bromoethane (1.0 mL) reacted to give1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹H NMR(CDCl₃, 500 MHz) δ 7.27 (d, 1H), 7.08 (dd, 1H), 6.99 (dd, 1H), 5.89 (s,2H), 4.18 (q, 2H), 2.04 (s, 6H), 1.53 (t, 3H); MS (ESI) 250 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (1.21 g, 4.8 mmol),acetic anhydride (5 mL), and hydriodic acid (0.07 mL, 0.83 mmol) reactedto give 3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as atan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.21 (d, 1H), 7.04-6.98 (m, 2H),6.29 (s, 1H), 4.17 (q, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.98 (s, 3H),1.52 (t, 3H); MS (ESI) 292 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (291 mg, 1.0mmol) and 3-cyclopropanecarbonyl chloride (0.18 mL, 2.0 mmol) reacted togive the product as a clear oil which was taken up in ether,precipitated with HCl in ether, and filtered to give6-(3-chloro-4-ethoxyphenyl)-1-(cyclopropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.70 (s,1H), 7.46-7.41 (m, 2H), 4.26 (q, 2), 2.99 (br s, 3H), 2.67-2.61 (m, 1H),2.58 (s, 3H), 2.52 (s, 3H), 1.43 (t, 3H), 1.28-1.12 (m, 4H); MS (ESI)356 (M+H)⁺.

EXAMPLE 406-(3-chloro-4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 39,3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (291 mg, 1.0mmol) and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give theproduct as a clear oil which was taken up in ether, precipitated withHCl in ether, and filtered to give 6-(3-chloro-4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochlorideas a green solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.71 (d, 1H), 7.63-7.57(m, 2H), 7.45-7.39 (m, 4H), 4.25 (q, 2H), 3.08 (br s, 3H), 2.44 (s, 3H),1.96 (s, 3H), 1.41 (t, 3H); MS (ESI) 406 (M+H)⁺.

EXAMPLE 411-(cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

To a solution of 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole(2.73 g, 10 mmol) (EXAMPLE 33) in CH₂Cl₂at rt (75 mL) was added a 1.0Msolution of boron tribromide in CH₂Cl₂ (15 mL, 15 mmol) and the reactionmonitored by LC. After complete consumption of the starting material,the reaction was carefully quenched with saturated NaHCO₃ andpartitioned between EtOAc and water. The organic layer was washed withbrine, dried over MgSO₄, filtered, concentrated in vacuo, and purifiedby flash chromatography to give3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole as a tansolid: ¹H NMR (CDCl₃, 500 MHz) δ 6.92 (d, 1H), 6.61 (d, 1H), 6.54 (dd,1H), 6.32 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.93 (s,3H), 1.69 (br s, 1H); MS (ESI) 260 (M+H)⁺.

Using the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole (1.37 g, 5.3mmol) and an excess of bromoethane (2.0 mL) reacted to give3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole as a tansolid: ¹H NMR (CDCl₃, 500 MHz) δ 6.99 (d, 1H), 6.59 (d, 1H), 6.53 (dd,1H), 6.31 (s, 1H), 4.08 (q, 2H), 3.74 (s, 3H), 2.41 (s, 3H), 2.25 (s,3H), 1.93 (s, 3H), 1.46 (t, 3H); MS (ESI) 288 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (241 mg, 0.84mmol) and 3-cyclopropanecarbonyl chloride (0.10 mL, 1.0 mmol) reacted togive the product which was taken up in ether, precipitated with HCl inether, and filtered to give1-(cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.29 (d,1H), 6.92 (d, 1H), 6.79 (dd, 2H), 4.18 (q, 2H), 3.77 (s, 3H), 3.45 (brs, 3H), 2.99 (br s, 3H), 2.64 (m, 1H), 2.46 (s, 3H), 1.40 (t, 3H),1.20-1.12 (m, 4H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 426-(4-ethoxy-2-methoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (EXAMPLE 34)(241 mg, 0.84 mmol) and p-toluoyl chloride (0.13 mL, 1.0 mmol) reactedto give the product as a clear oil which was taken up in ether,precipitated with HCl in ether, and filtered to give6-(4-ethoxy-2-methoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.59-7.53(m, 2H), 7.46-7.42 (m, 2H), 7.28 (d, 1H), 6.88 (d, 1H), 6.76 (dd, 1H),4.15 (q, 2H), 3.75 (s, 3H), 3.56 (br s, 3H), 3.10 (br s, 3H), 2.43 (s,3H), 1.89 (s, 3H), 1.38 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 436-(4-ethoxy-2-methoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride

Utilizing the general procedure outlined in EXAMPLE 1,3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (EXAMPLE 35)(241 mg, 0.84 mmol) and p-anisoyl chloride (0.15 mL, 1.0 mmol) reactedto give the product as a clear oil which was taken up in ether,precipitated with HCl in ether, and filtered to give6-(4-ethoxy-2-methoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.69-7.62(m, 2H), 7.29 (d, 1H), 7.19-7.13 (m, 2H), 6.90 (d, 1H), 6.77 (dd, 1H),4.16 (q, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.65 (br s, 3H), 3.05 (br s,3H), 1.93 (s, 3H), 1.38 (t, 3H); MS (ESI) 418 (M+H)⁺.

EXAMPLE 444-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid hydrazide

To a solution of5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoicacid methyl ester (100 mg, 0.26 mmol) (EXAMPLE 31) in ethanol (1 mL) wasadded excess hydrazine (0.1 mL). The solution was stirred overnight at50° C. and concentrated in vacuo to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid hydrazide as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 9.04 (br s,1H), 7.12-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.11 (q, 2H), 3.78 (br s,2H), 3.15 (t, 2H), 2.78 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 2.32 (t,2H), 2.18-2.12 (m, 2H), 1.48 (t, 3H); MS (ESI) 382 (M+H)⁺.

EXAMPLE 454-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid potassium salt

To a solution of4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid methyl ester (104 mg, 0.27 mmol) (EXAMPLE 31) in THF (3 mL) wasadded potassium trimethylsilanoate (57 mg, 0.4 mmol). The mixture wasstirred overnight and filtered to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyricacid potassium salt as a tan solid: ¹NMR (DMSO-d₆, 500 MHz) δ 7.27 (d,2H), 7.12 (d, 2H), 4.12 (q, 2H), 2.90 (t, 2H), 2.64 (s, 3H), 2.37 (s,3H), 2.36 (s, 3H), 1.91 (t, 2H), 1.80-1.75 (m, 2H), 1.37 (t, 3H); MS(ESI) 368 (M+H)⁺.

EXAMPLE 464-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid hydrazide

Utilizing the general procedure outlined in EXAMPLE 44,4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-4oxo-butyricacid methyl ester (100 mg, 0.27 mmol) (EXAMPLE 32) and excess hydrazine(0.1 mL) reacted to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid hydrazide as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.62 (br s,1H), 7.13-7.08 (m, 2H), 7.07-7.04 (m, 2H), 4.12 (q, 2H), 3.49 (t, 2H),3.09 (br s, 2H), 2.91 (t, 2H), 2.83 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3),1.49 (t, 3H); MS (ESI) 368 (M+H)⁺.

EXAMPLE 474-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid potassium salt

Utilizing the general procedure outlined in EXAMPLE 45,4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid methyl ester (100 mg, 0.27 mmol) (EXAMPLE 32) and potassiumtrimethylsilanoate (57 mg, 0.4 mmol) reacted to give4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionicacid potassium salt as a tan solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.27 (d,2H), 7.12 (d, 2H), 4.12 (q, 2H), 3.09 (dd, 2H), 2.63 (s, 3H), 2.36 (s,3H), 2.35 (s, 3H), 2.15 (dd, 2H), 1.37 (t, 3H); MS (ESI) 354 (M+H)⁺.

EXAMPLE 481,4,5,7-tetramethyl-6-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazine

A solution of 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and4-trifluoromethoxy aniline (170 μL, 1.26 mmol) was refluxed in EtOH (5mL)/AcOH (1%) for 48 h. Hydrazine (100 μL, 3.15 mmol) was added and themixture was refluxed for 1 h. The reaction mixture was poured into icewater (50 mL). The resulting precipitate was filtered and dried undervacuum to afford1,4,5,7-tetramethyl-6-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazineas a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.42 (d, 2H), 7.25 (d, 2H),2.81 (s, 6H), 2.41 (s, 6H); MS (ESI) 336 (M+H)⁺.

EXAMPLE 496-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48,1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-isopropyl aniline(172 μL, 1.26 mmol) reacted to give6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine asa tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.40 (d, 2H), 7.07 (d, 2H),3.01-2.97 (m, 1H) 2.83 (s, 6H), 2.41 (s, 6H) 1.28 (d, 6H); MS (ESI) 294(M+H)⁺.

EXAMPLE 50 6-(4-ethoxy)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48,1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and p-phenetidine (172 μL,1.26 mmol) reacted to give6-(4-ethoxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as atan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d,2H), 4.07 (q, 2H), 2.83 (s, 6H), 2.41 (s, 6H) 1.45 (t, 6H); MS (ESI) 294(M+H)⁺.

EXAMPLE 51 6-(2-ethoxy)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48,1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and o-phenetidine (172 μL,1.26 mmol) reacted to give6-(2-ethoxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as atan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d,2H), 4.12 (q, 2H), 2.83 (s, 6H), 2.41 (s, 6H) 1.55 (t, 6H); MS (ESI) 294(M+H)⁺.

EXAMPLE 526-(4-hydroxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48,1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-aminophenol (172 μL,1.26 mmol) reacted to give6-(4-hydroxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as atan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d,2H), 2.83 (s, 6H), 2.41 (s, 6H); MS (ESI) 266 (M+H)⁺.

EXAMPLE 536-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-isopropyl aniline(172 μL, 1.26 mmol) reacted to give6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine asa tan solid. ¹H NM (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d,2H), 3.01-2.97 (m, 1H) 2.83 (s, 6H), 2.41 (s, 6H) 1.28-1.27 (d, 6H). MS294 (M+H).

EXAMPLE 546-(6-Ethoxy-pyridin-3-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 6-ethoxy-pyridin-3-ylamine (140 mg, 1.0 mmol) reacted to give6-(6-Ethoxy-pyridin-3-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.04 (s, 1H), 7.41 (d,1H), 6.93 (d, 1H), 4.46 (q, 1H), 2.80 (s, 6H), 2.45 (s, 6H), 1.46 (t,3H); MS (ESI) 297 (M+H)⁺.

EXAMPLE 556-(5-Ethoxy-pyrazin-2-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2

-tetraacetylethane (200 mg, 1.0 mol) and 5-ethoxy-pyrazin-2-yl amine(130 mg, 1.0 mmol) reacted to give6-(5-ethoxy-pyrazin-2-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.27 (s, 1H), 8.11 (s,1H), 4.50 (q, 1H), 2.80 (s, 6H), 2.48 (s, 6H), 1.50 (t, 3H); MS (ESI)298 (M+H)⁺.

EXAMPLE 561,4,5,7-Tetramethyl-6-(5-propoxy-pyridin-2-yl)-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (100 mg, 0.5 mol) and 5-ethoxy-pyrazin-2-ylamine (80 mg, 0.5 mmol) reacted to give1,4,5,7-tetramethyl-6-(5-propoxy-pyridin-2-yl)-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.35 (s, 1H), 7.44 (d, 1H),7.22 (d, 1H), 4.08 (t, 2H), 2.80 (s, 6H), 2.45 (s, 6H), 1.89 (q, 2H),1.10 (t, 3H); MS (ESI) 311 (M+H)⁺.

EXAMPLE 572-Chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outline in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-2-chloro-phenolamine (144 mg, 1.0 mmol) reacted to give1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas yellow solid: MS (ESI) 306 (M+H)⁺.

To a solution of1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(340 mg, 1.0 mmol) was added hydrazine (50 μL). After stirring at rt for1 h, the reaction mixture was poured into ice water (25 mL). Theresulting precipitate was filtered, washed with diethyl ether (20 mL),and then dried under vacuum to afford2-chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol asa pale yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m,2H), 2.83 (s, 6H), 2.52 (s, 6); MS (ESI) 302 (M+H)⁺.

EXAMPLE 586-(2,4-Dimethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305mg, 2.0 mmol) and hydrazine (200 μL) reacted to give1,4,5,7-tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine asyellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.67 (m, 2H), 3.89(s, 3H), 3.78 (s, 3H), 2.80 (s, 6H), 2.40 (s, 6H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 596-(4-Isopropoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (100 mg, 0.5 mol), 2,4-dimethoxyaniline (76mg, 0.5 mmol) and hydrazine (50 μL) reacted to give6-(4-Isopropoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12 (d, 2H), 7.07 (d, 2H),4.68 (m, 1H), 2.86 (s, 6H), 2.47 (s, 6H), 1.45 (d, 6H); MS (ESI) 310(M+H)⁺.

EXAMPLE 601,4,57-Tetramethyl-6-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol),2-methyl-4-(trifluoromethoxy) aniline (191 mg, 1.0 mmol) and hydrazine(50 μL) reacted to give1,4,5,7-Tetramethyl-6-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.27 (s, 1H), 8.11 (s,1H), 4.50 (q, 1H), 2.80 (s, 6H), 2.48 (s, 6H), 1.50 (t, 3H); MS (ESI)298 (M+H)⁺; MS (ESI) 350 (M+H)⁺.

EXAMPLE 612-Methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (400 mg, 2.0 mol) and 4-amino-o-cresol (250mg, 2.0 mmol) reacted to give1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas yellow solid: MS (ESI) 286 (M+1)⁺.

To a solution of1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(100 mg, 0.32 mmol) in ethanol (5 mL) was added hydrazine (20 μL). Afterstirring at rt for 1 h, the reaction mixture was poured into ice water(25 mL). The resulting precipitate was filtered, washed with diethylether (20 mL), and then dried under vacuum to afford2-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol asa pale yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.09 (d, 1H), 7.03 (s,1H), 6.97 (d, 1H), 3.00 (s, 6H), 2.59 (s, 6H), 2.34 (s, 3H); MS (ESI)282 (M+H)⁺.

EXAMPLE 626-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 5-ethoxy-pyrazin-2-yl amine(151 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give6-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.76 (s,1H), 6.70 (d, 1H), 4.36 (br m, 4H), 2.83 (s, 6H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 633-Methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-3-methyl-phenol(123 mg, 1.0 mmol) reacted to give1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas a brown solid: MS (ESI) 306 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(323 mg, 1.0 mmol) and hydrazine (50 μL) reacted to afford3-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol asbrown solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m, 2H),2.83 (s, 6H), 2.52 (s, 6H); MS (ES) 302 (M+H)⁺.

EXAMPLE 646-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(prepared as outline in Example 57; 80 mg, 0.27 mmol) in 3 mL of dry DMFwas added bromoethane (54 mg, 0.5 mmol) and K₂CO₃ powder (50 mg). Theresulting reaction mixture was warmed to 50° C. and stirred for 1 h. Itwas quenched by addition of 20 mL of H₂O, extracted with diethyl ether(20 mL×2). The combined organic extracts were washed with brine (50 mL),dried (MgSO₄), filtered, and concentrated in vacuo to afford1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 302 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneand hydrazine reacted to give6-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.47 (s, 1H), 7.32 (d, 1H),7.25 (d, 1H), 4.27 (q, 2H), 2.79 (s, 6H), 2.48 (s, 6H), 1.53 (t, 3H); MS(ESI) 330 (M+H)⁺.

EXAMPLE 656-(4-Ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(prepared as outline in Example 63; 56 mg, 0.20 mmol) in 2 mL of dry DMFwas added bromoethane (100 μL) and K₂CO₃ powder (50 mg). The resultingreaction mixture was warmed to 50° C. and stirred for 1 h. It wasquenched by addition of 20 mL of H₂O, extracted with diethyl ether (20mL×2). The combined organic extracts were washed with brine (50 mL),dried (MgSO₄), filtered, and concentrated in vacuo to afford1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 314 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneand hydrazine reacted to give6-(4-ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₉, 500 MHz) δ 7.06 (d, 1H), 6.94 (s,1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s,3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 666-[4-(2-Fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

As outlined in Example 65,1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(20 mg) reacted with 1-bromo-2-fluoro ethane (50 μL), in the presence ofK₂CO₃ powder (50 mg), to afford1-{4-acetyl-1-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-2,5-dimethyl-1H-pyrrol-3-yl}-ethanone:MS (ESI) 332 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneand hydrazine reacted to give6-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.94 (s,1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s,3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 671,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine

As outlined in Example 65,1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(Example 52, 20 mg) reacted with 1-bromo-propane (100 μL), in thepresence of K₂CO₃ powder (50 mg), to afford1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone:MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanoneand hydrazine reacted to give1,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine aslight yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (d, 1H), 6.95 (br s,1H), 6.91 (d, 1H), 4.03 (t, 2H), 2.85 (s, 6H), 2.42 (s, 6H), 1.86 (q,2H), 1.79 (s, 3H), 1.09 (t, 3H); MS (ESI) 328 (M+H)⁺.

EXAMPLE 686-(4-Allyloxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

As in Example 65,1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(Example 52, 20 mg) reacted with allyl bromide (50 μL), in the presenceof K₂CO₃ (50 mg), to afford1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 326 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(20 mg) and hydrazine (50 μL) reacted to give6-(4-allyloxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine aslight yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (m, 1H), 6.98 (s,1H), 6.94 (m, 1H), 6.13 (m, 1H), 5.52 (d, 1H), 5.39 (d, 1H), 4.64 (d,2H), 2.81 (s, 6H), 2.35 (s, 6H), 1.84 (s, 3H); MS (ESI) 322 (M+H)⁺.

EXAMPLE 696-(4-ethoxy-3-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(prepared as in Example 61) (90 mg, 0.32 mmol) in 3 mL of dry DMF wasadded bromoethane (108 mg, 1.0 mmol) and K₂CO₃ powder (50 mg). Theresulting reaction mixture was warmed to 50° C. and stirred for 1 h. Itwas quenched by addition of 20 mL of H₂O, extracted with diethyl ether(20 mL×2). The combined organic extracts were washed with brine (50 mL),dried (MgSO₄), filtered, and concentrated in vacuo to afford1-[4-acetyl-1-(4-ethoxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 314 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(99 mg, 0.32 mmol) and hydrazine (50 μL) reacted to give6-(4-ethoxy-3-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 6.96 (m, 3H), 4.15 (q, 2H),2.80 (s, 6H), 2.49 (s, 6H), 2.32 (s, 3H), 1.52 (t, 3H); MS (ESI) 310(M+H)⁺.

EXAMPLE 706-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305mg, 2.0 mmol) reacted to give1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas yellow solid: MS (ESI) 316 (M+H)⁺.

To a stirring solution of crude1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneprepared as above (90 mg, 0.3 mmol) in 5.0 mL of CH₂Cl₂ at 0° C. wasadded BBr₃ (1.0 M in CH₂Cl₂, 0.9 mL, 0.9 mmol). After 1 h at 0° C., itwas warmed to rt and stirred for an additional 2 h before it wasquenched with saturated aq. NaHCO₃ solution (5 mL). It was extractedwith EtOAc (2×10 mL), and the combined organic extracts were washed withdried with MgSO₄, filtered, and concentrated in vacuo to afford thecrude product as a yellow oil. This crude material was purified byautomated chromatography on silica gel (using 20-50%EtOAc/hexanesgradient) to give the major product1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas pale yellow oil: MS (ESI) 302 (M+H)⁺; In this reaction, small amount(˜10%) of minor product1-[4-acetyl-1-(2,4-dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanonewas also isolated as clear colorless oil: MS (ESI) 288 (M+H)⁺.

Utilizing the general procedure outlined in Example 65,1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in thepresence of K₂CO₃ (50 mg), to afford1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 330 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(60 mg) and hydrazine (50 μL) reacted to give6-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.66 (m,2H), 4.05 (q, 2H), 3.86 (s, 3H), 2.84 (s, 6H), 2.41 (s, 6H), 1.25 (t,3H); MS (ESI) 326 (M+H)⁺

EXAMPLE 716-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 65,1-[4-acetyl-1-(2,4dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneprepared as in Example 70 (12 mg, 0.4 mmol) reacted with bromoethane (30μL, excess), in the presence of K₂CO₃ (10 mg), to afford1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 344 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(4 mg) and hydrazine (5 μL) reacted to give6-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (d, 1H), 6.67 (s,1H), 6.64 (d, 1H), 4.15 (q, 1H), 4.04 (q, 1H), 2.89 (br s, 6H), 2.43 (s,6H), 1.49 (t, 3H, 1.26 (t, 3H); MS (ESI) 340 (M+H)⁺.

EXAMPLE 726-(2-ethoxy-4-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a stirring solution of1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneprepared as in Example 70 (1580 mg, 0.5 mmol) in 2.0 mL of dry DMF at rtwas added sodium ethanethiolate (80%, Aldrich; 210 mg, 2.0 mmol). After20 min at rt, it was heated to 120° C. and stirred for an additional 2 hbefore it was quenched with 1N HCl (5 mL). It was extracted with EtOAc(2×10 mL), and the combined organic extracts were washed with dried withMgSO₄, filtered, and concentrated in vacuo to afford the crude productas a yellow oil. This crude material was purified by automatedchromatography on silica gel (using an 20-50% EtOAc/hexanes gradient) togive the major product1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas pale yellow oil: MS (ESI) 302 (M+H)⁺.

Utilizing the general procedure outlined in Example 65,1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in thepresence of K₂CO₃ (50 mg), to afford1-[4-acetyl-1-(2-ethoxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 330 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(60 mg) and hydrazine (50 μL) reacted to give6-(2-ethoxy-4-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (d, 1H), 6.68 (s,1H), 6.64 (d, 1H), 4.15 (q, 1H), 3.78 (s, 3H), 2.81 (s, 6H), 2.40 (s,6H), 1.51 (t, 3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 736-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (300 mg, 1.5 mol) and 4-amino-2.3-xylenol (206mg, 1.5 mmol) reacted to give1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas yellow solid: MS (ESI) 300 (M+H)⁺.

Utilizing the general procedure outlined in Example 65,1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in thepresence of K₂CO₃ (50 mg), to afford1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(108 mg, 0.3) and hydrazine (50 μL) reacted to give6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.92 (d, 1H), 6.86 (d,1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s,3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 746-(4-Ethoxy-2,5-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 481, 1,1,2,2

-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-2,5-dimethylphenol (138mg, 1.0 mmol) reacted to give1-[4-acetyl-1-(4-hydroxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanoneas yellow solid: MS (ESI) 300 (M+H)⁺.

Utilizing the general procedure outlined in Example 7,1-[4-acetyl-1-(4-hydroxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in thepresence of K₂CO₃ (50 mg), to afford1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone:MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example48,1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone(108 mg, 0.3) and hydrazine (50 μL) reacted to give6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazineas an off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.88 (s, 1H), 6.77 (s,1H), 4.14 (q, 2H), 2.85 (s, 6H), 2.39 (s, 6H), 2.26 (s, 3H), 1.83 (s,3H, 1.50 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 756-(4-Ethoxy-2-fluoro-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10.0 mmol) in 20 mL ofdry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder (500mg). The resulting reaction mixture was warmed to 50° C. and stirred for1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethylether (100 mL×2). The combined organic extracts were washed with brine(50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford4-ethoxy-2-fluoro-1-nitrobenzene as a pale yellow oil: MS (ESI) 186(M+H)⁺.

To a solution of 4-ethoxy-2-fluoro-1-nitro benzene (1.0 g, 5.4 mmol) inabsolute EtOH (25 mL) at rt was added 250 mg of Pd/C (Aldrich, 10 wt. %on activated carbon), followed by slow addition of hydrazine hydrate(2.5 mL). The resulting reaction mixture was refluxed at 90° C. for 30min. It then cooled to rt, filtered through Celite, and thenconcentrated in vacuo to afford 4-ethoxy-2-fluoro-phenyl amine as a paleyellow oil: MS (ESI) 156 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 4-ethoxy-2-fluoro-phenylamine (155 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give6-(4-ethoxy-2-fluoro-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13 (t, 1H), 6.88 (m, 2H),4.16 (q, 2H), 2.82 (s, 6H), 2.46 (s, 6H), 1.53 (t, 3H); MS (ESI) 314(M+H)⁺.

EXAMPLE 766-(4-Ethoxy-2-methylsulfanyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 4-Ethoxy-2-fluoro-1-nitro benzene prepared as inExample 75 (185 mg, 1.0 mmol) in 2 mL of dry DMF was added NaSMe (84 mg,1.20 mmol). The resulting reaction mixture was warmed to 50° C. andstirred for 1 h. It was quenched by addition of 20 mL of H₂O. Theprecipitate was filtered, washed with H₂O and dried under vacuum toafford 4-ethoxy-2-methylsulfanyl-1-nitro-benzene as yellow oil: MS (ESI)211 (M+H)⁺.

To a solution of 4-ethoxy-2-methylsulfanyl-1-nitro-benzene (1.0 g, 5.4mmol) in absolute EtOH (25 mL) at rt was added 40 mg of Pd/C (Aldrich,10 wt. % on active carbon), followed by slow addition of hydrazinehydrate (0.5 mL). The resulting reaction mixture was refluxed at 90° C.for 3 h. It then cooled to rt, filtered through Celite, and thenconcentrated in vacuo to afford 4-ethoxy-2-methylsulfanyl-phenyl amineas a pale yellow oil: MS (ESI) 184 (M+H)⁺.

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (200 mg, 1.0 mol),4-ethoxy-2-methylsulfanyl-phenyl amine (140 mg, 0.8 mmol) and hydrazine(50 μL) reacted to give6-(4-Ethoxy-2-methylsulfanyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05 (d, 1H), 6.88 (s, 1H),6.82 (d, 1H), 4.16 (q, 2H), 2.81 (s, 6H), 2.42 (s, 6H), 1.53 (t, 3H); MS(ESI) 342 (M+H)⁺.

EXAMPLE 776-(4-Ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder(500 mg). The resulting reaction mixture was warmed to 50° C. andstirred for 1 h. It was quenched by addition of 20 mL of H₂O, extractedwith diethyl ether (2×20 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuoto afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: ¹HNMR (CDCl₃, 500 MHz) δ 8.20 (d, 1H), 7.36 (s, 1H), 6.89 (m, 1H), 5.00(s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).

To a solution of (5-ethoxy-2-nitro-phenyl)-methanol (592 mg, 3.0 mmol)in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt.% on active carbon), followed by slow addition of hydrazine hydrate (1.5mL). The resulting reaction mixture was refluxed at 90° C. for 1 h. Itwas then cooled to rt, filtered through Celite, and then concentrated invacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a paleyellow oil: MS (ESI) 168 (M+H)⁺.

A solution of 1,1,2,2-tetraacetylethane (600 mg, 3.0 mol) and(2-amino-5-ethoxy-phenyl)-methanol (496 mg, 3.0 mmol) was refluxed inEtOH (10 mL)/AcOH (1%) for 14 h. It was cooled to rt, and anhydroushydrazine (200 μL, 6.3 mmol) was added. After stilling at rt for 1 h,the reaction mixture was poured into ice water (50 mL). The resultingprecipitate was filtered, washed with diethyl ether (20 mL), and thendried under vacuum to afford[5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-phenyl]-methanolas a pale yellow solid: 1H NMR (CDCl₃, 500 MHz) δ 7.24 (s, 1H), 6.98 (m,2H), 4.62 (s, 2H), 4.16 (q, 2H), 2.66 (s, 6H), 2.41 (s, 6H), 1.50 (t,3H); MS (ESI) 327 (M+H)⁺.

To a solution of[5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol(70 mg, 2.3 mmol) in CH₂Cl₂ (10 mL) at rt was added MnO₂ (200 mg,excess). The resulting reaction mixture was stirred at rt for 2 h beforeif was filtered through Celite, and eluted with CH₂Cl₂ (20 mL×2). Theeluant was collected and concentrated in vacuo to afford5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-benzaldehydeas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 10.56 (s, 1H), 7.71 (s,1H), 7.40 (d, 1H), 7.20 (d, 1H), 4.28 (q, 2H), 2.86 (s, 6H), 2.45 (s,6H), 1.58 (t, 3H); MS (ESI) 325 (M+H)⁺.

A suspension of methyltriphenylphosphonium bromide (178 mg, 0.5 mmol) in3.0 mL of THF at rt was treated with n-BuLi (1.6 M in Hexane, 280 μL,0.45 mmol) dropwise. After 5 min at rt, it was warmed to 50° C. andstirred for 30 min, and then cooled back to rt to give the in situgenerated ylide solution. Part of this reaction solution (2.0 mL) wastransferred to another reaction flask containing5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-benzaldehyde(32 mg, 0.1 mol) and 0.5 mL of THF under N₂ atmosphere. The resultingreaction mixture was stirred at rt for 3 h before it was quenched withH₂O and extracted with diethyl ether (2×10 mL). All organic extractswere combined, dried (MgSO₄), filtered, and concentrated in vacuo toafford crude product as yellow oil. It was purified by preparative TLCplate (20×20 cm, 0.5 mm layer thickness, eluted with 7% CH₂Cl₂/MeOH) togive pure6-(4-ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-δ]pyridazineas a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.26 (s, 1H), 7.06 (d,1H), 6.98 (d, 1H), 5.79 (dd, 1H), 5.77 (d, 1H), 5.24 (d, 2H), 4.15 (q,2H), 2.81 (s, 6H), 2.37 (s, 6H), 1.52 (t, 3H); MS (ESI) 323 (M+H)⁺.

EXAMPLE 786-(4-Ethoxy-2-ethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of6-(4-ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine(30 mg, 3.0 mmol) in 3 mL of ethanol was added anhydrous hydrazine (20μL). The resulting reaction solution was refluxed at 90° C. for 90 min.It was allowed to warm to rt and directly condensed in vacuo to afford6-(4-Ethoxy-2-ethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazineas a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.00 (m, 2H), 6.89(m, 1H), 4.15 (q, 2H), 2.82 (s, 6H), 2.38 (s, 6H), 2.10 (q, 2H), 1.52(t, 3H), 1.08 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 796-(4-Ethoxy-2,6-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 77,4-nitro-3,5-dimethyl-phenol was converted to4-ethoxy-2,6-dimethyl-phenylamine in two step. This crude amine was usedirectly in the next reaction without further purification.

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (308 mg, 1.56 mol),4-ethoxy-2,6-dimethyl-phenylamine (250 mg, 1.0 mmol) and hydrazine (100μL) reacted to give6-(4-ethoxy-2,6-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazineas yellow solid: ¹H NM (CDCl₃, 500 MHz) δ 6.81 (s, 1H), 6.75 (s, 1H),4.04 (q, 2H), 2.82 (s, 6H), 2.44 (s, 6H), 2.47 (s, 3H), 2.35 (s, 6H),1.79 (s, 3H), 1.88 (t, 3H), ; MS (ESI) 324 (M+H)⁺.

EXAMPLE 80[5-Ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3.4-d]pyridazin-6-yl)-phenyl]-methanol

To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder(500 mg). The resulting reaction mixture was warmed to 50° C. andstirred for 1 h. It was quenched by addition of 20 mL of H₂O, extractedwith diethyl ether (2×20 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuoto afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: ¹HNMR (CDCl₃, 500 MHz ) δ 8.20 (d, 1H), 7.36 (s, 1H), 6.89 (m, 1H), 5.00(s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).

To a solution of (5-ethoxy-2-nitro-phenyl)-methane (592 mg, 3.0 mmol) inabsolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. %on activated carbon), followed by slow addition of hydrazine hydrate(1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1h.It then cooled to rt, filtered through Celite, and then concentrated invacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a paleyellow oil: MS (ESI) 168 (M+H)⁺.

A solution of 1,1,2,2-tetraacetylethane (600 mg, 3.0 mol) and(2-amino-5-ethoxy-phenyl)-methanol (496 mg, 3.0 mmol) was refluxed inEtOH (10 mL)/AcOH (1%) for 14 h. It was cooled to rt, and anhydroushydrazine (200 μL, 6.3 mmol) was added. After stirring at rt for 1 h,the reaction mixture was poured into ice water (50 mL). The resultingprecipitate was filtered, washed with diethyl ether (20 mL), and thendried under vacuum to afford[5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanolas a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.22 (s, 1H), 6.95 (m,2H), 4.40 (s, 2H), 4.16 (q, 2H), 2.66 (s, 6H), 2.41 (s, 6H), 1.50 (t,3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 81[2-Ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3.4-d]pyridazin-6-yl)-phenyl]-methanol

Utilizing the general procedure outlined in Example 77,2-hydroxymethyl-4-nitro-phenol was converted to afford(5-amino-2-ethoxy-phenyl)-methanol in two step. This crude amine was usedirectly in the next reaction without further purification.

Utilizing the general procedure outlined in Example 48,1,1,2,2-tetraacetylethane (308 mg, 1.56 mol),(5-amino-2-ethoxy-phenyl)-methanol (250 mg, 1.0 mmol) and hydrazine (100μL) reacted to give[2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanolas yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.24 (s, 1H), 7.08-7.01 (m,2H), 4.81 (s, 2H), 4.18 (q, 2H), 2.77 (s, 6H), 2.43 (s, 6H), 1.51 (t,3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 825-Ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde

To a solution of[5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol(prepared as described in Example 81; 70 mg, 2.3 mmol) in CH₂Cl₂ (10 mL)at rt was added MnO₂ (200 mg, excess). The resulting reaction mixturewas stirred at rt for 2 h before if was filtered through Celite, andeluted with CH₂Cl₂ (2×20mL). The eluant was collected and concentratedin vacuo toafford5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4δ]pyridazin-6-yl)-benzaldehydeas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 10.55 (s, 1H), 7.70 (s,1H), 7.40 (d, 1H), 7.20 (d, 1H), 4.30 (s, 2H), 2.87 (s, 6H), 2.45 (s,6H), 1.57 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 832-Ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde

Utilizing the general procedure outlined in Example 82,[5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol(prepared as described in Example 81; 100 mg, 0.3 mmol) reacted withMnO₂ (200 mg, excess) to afford2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehydeas a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 9.20 (s, 1H), 7.57 (s, 1H),7.34 (d, 1H), 7.24 (d, 1H), 4.20 (q, 2H), 2.90 (s, 6H), 2.42 (s, 6H),1.51 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 846-(4-ethoxy-2-nitrophenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4d]pyridazinehydrochloride

To a solution of acetonyl acetone (1.95 mL, 16.5 mmol) in acetic acid(100 mL) was added 4-ethoxy-2-nitroaniline (3.0 g, 16.5 mmol) and thered mixture heated at reflux overnight. After cooling to rt, the nowblack solution was poured into water and extracted with EtOAc (2×200mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to an oil. Purification by flashchromatography (10% EtOAc/hexanes) gave2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a red oil: ¹H NMR(CDCl₃, 500 MHz) δ 7.46 (d, 1H), 7.27 (t, 1H), 7.19 (dd, 1H), 5.91 (s,2H), 4.15 (q, 1H), 1.96 (s, 6H), 1.50 (t, 3H); MS (ESI) 261 (M+H)⁺.

To a solution of 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole (3.10 g,11.9 mmol) in CH₂Cl₂ (80 mL) at 0° C. was added acetyl chloride (2.13mL, 30 mmol) followed by dropwise addition of tin(IV) chloride (3.51mL,30 mmol). The solution was allowed to warm to rt overnight followed byheating at reflux for an addition 24 hours. After cooling to rt, thereaction was diluted with 0.25 M NaOH, extracted with EtOAc, the organiclayer washed with brine, dried over MgSO₄, filtered, concentrated invacuo, and purified by flash chromatography (20-75% EtOAc/hexanes) togive 3,4-diacetyl-2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as agreen solid (MS (ESI) 345 (M+H)⁺; the major product beingmonoacylation). The solid was taken up in ethanol (10 mL), an excess ofhydrazine (0.1 mL) added, and the solution heated at 50° C. After 3hours, the reaction was poured over ice, filtered, taken up in hotether, precipitated with HCl in ether, and filtered to give6-(4-ethoxy-2-nitrophenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinehydrochloride as a tan solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.93 (d, 1H),7.68-7.61 (m, 2H), 4.29 (q, 1H), 3.02 (br s, 3H), 2.82 (br s, 3H), 2.46(s, 6H), 1.42 (t, 3H); MS (ESI) 341 (M+H)⁺.

EXAMPLE 856-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

To a slurry of NaH (2.6 g, 66 mmol, 60% dispersion in mineral oil) andTHF (200 mL) at 0° C. was added ethyl acetoacetate (7.8 mL, 60 mmol)dropwise. After 15 min, α-chloroacetone (5.2 mL, 66 mmol) was added andthe resulting solution allowed to warm to rt over 12 h. The reactionmixture was partitioned between MTBE and water, the water layerextracted with MTBE (2×50 mL), and the combined extracts dried (MgSO₄),and concentrated under reduced pressure to afford, after automatedchromatography on silica gel (using an EtOAc/hexanes gradient), ethyl2-acetyl-4-oxopentanoate as a colorless oil.

Ethyl 2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20mL of EtOH. p-Phenetidine (4.70 g, 34.2 mmol) was added as well asseveral drops of AcOH and heated at reflux for 15 h. The reactionmixture was allowed to cool to rt and then concentrated under reducedpressure. The resulting brown oil was dissolved in CH₂Cl₂ (20 mL) andwashed with saturated aqueous NaHCO₃ (3×50 mL) dried (MgSO₄) andconcentrated. The resulting crude ethyl1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was taken onwithout further purification. MS (ESI) 288 (M+H)⁺.

In an oven-dried flask, ethyl1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (9.32 g, 32.5mmol) combined with toluene (100 mL), acetyl chloride (2.8 mL, 39.3mmol), and SnCl₄ (4.67 mL, 29.3 mmol). The reaction mixture was stirredat rt for 4 h. The reaction was quenched by the addition of 1N NaOH(added until pH 12 was reached) and the aqueous layer extracted withCH₂Cl₂ (2×200 mL) and Et₂O (2×100 mL). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo. The resulting crude(ethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate)was of sufficient purity for further reactions. MS (ESI) 330 (M+H)⁺.

A solution ofethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate(7.50 g, 22.8 mmol) and EtOH (75 mL) was placed in a resealable reactionvessel. Hydrazine (2 mL, 64 mmol) and AcOH (˜1 mL) were added, the tubeclosed, and heated to 80° C. for 12 h. The resulting slurry was allowedto cool to rt and poured into ice water (50 mL). The resulting whitesolid(6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one)was filtered and dried under vacuum for 8 h. MS (ESI) 298 (M+H)⁺.

A solution of POCl₃ (15 mL) and6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one(1.5 g) were combined and heated at reflux for 48 h. The reactionmixture was allowed to cool to rt, and was quenched by the carefuladdition of water (50 mL) followed by a saturated aqueous solutionNaHCO₃ (50 mL). The reaction mixture was extracted with CH₂Cl₂ (5×50mL), and the combined organic extracts were dried (MgSO₄) andconcentrated under reduced pressure to yield1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a yellow/green solid. MS (ESI) 316 (M+H)⁺.

To a Personal Chemistry Microwave Synthesizer microwave vial wascombined1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine(200 mg, 0.64 mmol), MeNH₂ (1 mL, 40% in H₂O), and EtOH (1 mL). The vialwas sealed and heated at 120° C. for 12 min. The reaction mixture waspoured into water to afford crude6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine.Purification by reverse phase preparative HPLC using a YMC CombiPrep ProC₁₈20×100 column (Gradient: 5%-100% Acetonitrile in a H₂O+0.1% TFAsolution over 10 min, retention time: 6.1 min) afforded pure6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amineas a colorless solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05-7.12 (m, 4H), 4.16(q, 2H), 3.20 (s, 3H), 2.69 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.51(t, 3H); MS (ESI) 311 (M+H)⁺.

EXAMPLE 866-(4-ethoxyphenyl)-N,N,4,5,7-pentamethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

Utilizing the general procedure outlined in EXAMPLE 85,1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineand Me₂N (1 mL, 40% solution in H₂O) reacted to give6-(4-ethoxyphenyl)-N,N,4,5,7-pentamethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine:¹H NMR (CDCl₃, 500 MHz) δ 7.06-7.15 (m, 4H), 4.15 (q, 2H), 3.08 (s, 6H),2.78 (s, 3H), 2.50 (s, 2H), 2.44 (s, 2H), 1.51-1.52 (s, 3H); MS (ESI)325 (M+H)⁺.

EXAMPLE 876-(3,5-dibromo-4-ethoxyphenyl)-1-aminomethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the procedure outlined in Example 85, ethyl2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20 mL ofEtOH. 2,6-dibromo-4-aminophenol (11.6g, 34.2mmol) were reacted to affordethyl1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylatewas taken on without further purification. MS (ESI) 418 (M+H)⁺.

Crude ethyl1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylatewas mixed with Cs₂CO₃ (11.4 g, 35 mmol), bromoethane (7.50 g, 70.0mmol), and MeCN (150 mL) and heated at 50 ° C. for 4 hr. Standardaqueous workup afforded, after purification on silica gel (utilizing anethyl acetate/hexanes gradient) ethyl1-(3,5-dibromo-4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate asa reddish solid. MS (ESI) 446 (M+H)⁺. This compound was processed as inexample 85 to afford6-(3,5-dibromo-4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amineas a colorless solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41 (s, 2H), 4.19 (q,2H), 3.13 (s, 3H), 2.62 (s, 3H), 2.59 (s, 3H), 2.40 (s, 3H), 1.54 (t,3H); MS (ESI) 469 (M+H)⁺.

EXAMPLE 886-(4-ethoxyphenyl)-1-(4-methoxyphenyl)amino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85,1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineand p-anisidine (0.40 mg, 0.32 mmol) reacted to give6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine:¹H NMR (CDCl₃, 500 MHz) δ 7.32 (d, 2H), 7.08 (d, 2H), 7.06 (d, 2H), 6.91(d, 2H), 4.12 (q, 2H), 3.81 (s, 3H), 2.69 (s, 3H), 2.55 (s, 3H), 1.50(t, 3H); MS (ESI) 403 (M+H)⁺.

EXAMPLE 896-(4-ethoxyphenyl)-1-aminophenyl-4.5.7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85,1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineand aniline (0.36 mg 0.32 mmol) reacted to give6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine:¹H NMR (CDCl₃, 500 MHz) δ 7.33-7.36 (m, 3H), 6.65-7.13 (m, 6H), 4.14 (q,2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H) 1.52 (t, 3H); MS (ESI) 403(M+H)⁺.

EXAMPLE 906-(4-ethoxyphenyl)-1-(4-methylphenyl)amino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85,1-chloro-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineand 4-methylaniline (0.40 mg, 0.32 mmol) reacted to give6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine:¹H NMR (CDCl₃, 500 MHz) δ 7.50 (d, 2H), 7.17 (d, 2H), 7.16 (d, 2H), 6.99(d, 2H), 4.16 (q, 2H), 2.81 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.21(s, 3H), 1.52 (t, 3H); MS (ESI) 423 (M+H)⁺.

EXAMPLES 91-367

Example 91-367 were synthesized in library mode.1-Chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine(50 mg per vessel) or1-Chloro-6-(2-methoxy-4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine(prepared as in example 85 utilizing 2-methoxy-4-ethoxy aniline) (50 mgper vessel), and polystyrene resin-bound N-methylmorpholine (1.1 eq.)were dry loaded into reaction vessels. Amines (2 eq.) in pyridine (1 mL)was added to the vessels. The vessels were capped and sealed. Thereactions were heated to 100 ° C. and agitated overnight. Additionalpolystyrene resin-bound N-methylmorpholine (2 eq.), polystyreneresin-bound chloroformate (2 eq.), and chloroform (4 mL) were added. Theresulting suspension was agitated at 50 ° C. overnight. The reactionsolutions were collected by filtration, concentrated and dried inGeneVac. The products were analyzed by LCMS.

MS Example Name Structure (ESI) Example 916-(4-ethoxy-2-methoxyphenyl)-N-(1H-indol-5-ylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

457 Example 92N-benzyl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

418 Example 93N-(1,3-dihydro-2-benzofuran-5-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

446 Example 941-(4-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}phenyl)imidazolidin-2-one

488 Example 956-(4-ethoxy-2-methoxyphenyl)-N-(3-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d[pyridazin-1-amine

434 Example 966-(4-ethoxy-2-methoxyphenyl)-N-(3-isopropylphenly)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

446 Example 97N-(3,5-dimethoxyphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

464 Example 986-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-phenyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

404 Example 996-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(3-pyridin-3-ylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

447 Example 1006-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-pyridin-2-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

433 Example 1016-(4-ethoxy-2-methoxyphenyl)-N-isopropyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

369 Example 1026-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[4-(methylthio)phenyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

450 Example 1036-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(4-methylbenzyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1046-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(pyridin-3-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

419 Example 1056-(4-ethoxy-2-methoxyphenyl)-N-(2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-3-ylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

476 Example 1064-(2-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}ethyl)phenol

448 Example 107N-(3-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}phenyl)acetamide

461 Example 1086-(4-ethoxy-2-methoxyphenyl)-N-(3-fluoro-4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

436 Example 1091-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperidine-4-carboxamide

439 Example 1106-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(pyridin-2-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

419 Example 111N-butyl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

384 Example 112N-(3,4-dimethoxybenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

478 Example 113N-(cyclohexylmethyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

424 Example 1146-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(tetrahydrofuran-2-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

412 Example 115N-(2,3-dihydro-1H-inden-1-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 1166-(4-ethoxy-2-methoxyphenyl)-N-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

434 Example 1176-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-methylbenzyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1186-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(3-phenylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

446 Example 119N-(2,3-dihydro-1H-inden-2-ylmethyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

458 Example 1206-(4-ethoxy-2-methoxyphenyl)-N-1H-indazol-6-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 1216-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(1-phenylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1226-(4-ethoxyphenyl)-N-1H-indol-5-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

413 Example 1236-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-methyl-1,3-benzothiazol-6-yl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

475 Example 124N-cyclopentyl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

396 Example 1256-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-phenylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

446 Example 1266-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(4-phenylbutyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

460 Example 1276-(4-ethoxy-2-methoxyphenyl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

436 Example 1286-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 1296-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

440 Example 1306-(4-ethoxy-2-methoxyphenyl)-N-(3-methoxybenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

448 Example 131N-(3,4-dimethoxyphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

464 Example 1326-(4-ethoxy-2-methoxyphenyl)-N-2H-indazol-5-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 1336-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(3-methylbenzyl)-6H-pyrrolo[3,4-d]pyrldazin-1-amine

432 Example 1346-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(spiro[2.5]oct-1-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

450 Example 135N-(2,2-dimethoxyethyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

416 Example 1366-(4-ethoxy-2-methoxyphenyl)-N-(2-furylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

407 Example 1376-(4-ethoxy-2-methoxyphenyl)-N-1H-indol-5-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

443 Example 1386-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(1-methylpiperidin-4-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

439 Example 1396-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(1-phenylpiperidin-4-yl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

487 Example 1406-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-phenylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1411-(4-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}phenyl)-3-methylimidazolidin-2-one

502 Example 1426-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[1-methyl-2-(1H-1,2,4-triazol-1-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

437 Example 143N-(2-ethoxybenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 1444-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine

460 Example 1456-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[2-(1H-pyrazol-1-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

422 Example 146N-(4-chlorobenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

452 Example 1476-(4-ethoxyphenyl)-N-1H-indazol-5-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

413 Example 1486-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[3-(trifluoromethyl)benzyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

486 Example 149(3-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}phenyl)methanol

434 Example 1506-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

475 Example 151N-(3-chlorobenzyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

422 Example 1526-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(1-methylpyrrolidin-3-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

425 Example 1536-(4-ethoxy-2-methoxyphenyl)-N-[2-(3-methoxyphenyl)ethyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 1546-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

422 Example 1556-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(pyrazolo[1,5-a]pyridin-7-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

458 Example 1566-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(4-phenoxyphenyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

496 Example 157N′-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-dimethylbenzene-1,4-diamine

447 Example 1586-(4-ethoxy-2-methoxyphenyl)-N-(3-isopropoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 1596-(4-ethoxy-2-methoxyphenyl)-N-(2-methoxyethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

385 Example 160N-(3-chloro-4-methylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

452 Example 1616-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

439 Example 162N-[2-(3-chlorophenyl)ethyl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

466 Example 163N-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 164N-cyclobutyl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

381 Example 165N-(3,4-dihydro-1H-isochromen-1-ylmethyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

474 Example 1666-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(3-morpholin-4-ylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

455 Example 1676-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-pyrazin-2-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

434 Example 1687-chloro-4-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine

494 Example 1696-(4-ethoxy-2-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 1706-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[3-(methylthio)phenyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

450 Example 171N-(1-benzylpiperidin-4-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

501 Example 1726-(4-ethoxy-2-methoxyphenyl)-N-(3-fluorobenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

436 Example 173N-cyclopropyl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

367 Example 174(3aR,9bR)-2-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,3a,4,5,9b-hexahydro-1H-benzo]e]isoindole

484 Example 1756-(4-ethoxy-2-methoxyphenyl)-N-(3-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 176N-(3,5-dimethylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1776-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-morpholin-4-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

441 Example 1786-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-(4-phenyl-1,4-diazepan-1-yl)-6H-pyrrolo[3,4-d]pyridazine

487 Example 1796-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

487 Example 1806-(4-ethoxy-2-methoxyphenyl)-N-(2-methoxybenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

448 Example 1813-benzyl-7-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

524 Example 182N′-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-diethylpropane-1,3-diamine

441 Example 1836-(4-ethoxy-2-methoxyphenyl)-N-(3-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

448 Example 1847-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

502 Example 185N-(3-chloro-4-methoxyphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

468 Example 1861-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

531 Example 1876-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(6-methylpyridin-2-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

433 Example 1886-(4-ethoxy-2-methoxyphenyl)-N-(4-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 1891-azetidin-1-yl-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

367 Example 190N-(3,4-dimethylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 191N-(3,4-difluorobenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

454 Example 1926-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(tetrahydrofuran-2-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

381 Example 1936-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-morpholin-4-yl-6H-pyrrolo[3,4-d]pyridazine

397 Example 1946-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}-6H-pyrrolo[3,4-d]pyridazin-1-amine

500 Example 1956-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(octahydro-2H-quinolizin-1-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

479 Example 196N-(3-chlorobenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

452 Example 1976-(4-ethoxy-2-methoxyphenyl)-N-[2-(2-methoxyphenyl)ethyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

462 Example 198N-(3-bromo-4-methylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

496 Example 1996-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[3-(2-methylpiperidin-1-yl)propyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

467 Example 2002-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,4,9-tetrahydro-1H-beta-carboline

483 Example 201N-(2,3-dihydro-1H-inden-1-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

414 Example 202N-(sec-butyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

384 Example 203N-(3,4-dichlorobenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

486 Example 2043-{4-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperazin-1-yl}phenyl

489 Example 2056-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-[(1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl]-6H-pyrrolo[3,4-d]pyridazine

464 Example 206N-[3-(benzyloxy)phenyl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

510 Example 2076-(4-ethoxyphenyl)-N-1H-indazol-5-yl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-aminiumchloride

450 Example 2086-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(1-piperidin-1-ylcyolohexyl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

507 Example 209N-butyl-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

353 Example 2106-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(quinolin-8-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

439 Example 2116-(4-ethoxy-2-methoxyphenyl)-N-(4-isopropylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

446 Example 2126-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[4-(trifluoromethyl)benzyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

486 Example 2136-(4-ethoxyphenyl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

406 Example 214N-[2-(4-chlorophenyl)ethyl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

466 Example 215N-(4-chlorobenzyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

422 Example 2161-[4-(2,5-dimethylphenyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

501 Example 2171-(4-benzylpiperazin-1-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

487 Example 2186-(4-ethoxyphenyl)-N-isopropyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

339 Example 2196-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

410 Example 220N-(3-chloro-4-morpholin-4-ylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

523 Example 221N-[(3-cyclopropyl-1H-pyrazol-5-yl)methyl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

418 Example 2226-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

501 Example 2236-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

391 Example 2246-(4-ethoxy-2-methoxyphenyl)-N-(isoquinolin-5-ylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

469 Example 2256-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-[2-(phenoxymethyl)morpholin-4-yl]-6H-pyrrolo[3,4-d]pyridazine

504 Example 2266-(4-ethoxyphenyl)-N-(1H-indol-4-ylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

427 Example 227N-(2,2-diphenylethyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

508 Example 228N-(4-tert-butylphenyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

460 Example 229N′-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-dimethylethane-1,2-diamine

399 Example 2306-(4-ethoxyphenyl)-N-[2-(3-methoxyphenyl)ethyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 2316-(4-ethoxyphenyl)-N-(2-methoxybenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

418 Example 2322-(2-{[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}ethyl)quinazolin-4(3H)-one

500 Example 2336-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

327 Example 2346-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-(4-pyridin-2-ylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

474 Example 2356-(4-ethoxy-2-methoxyphenyl)-N-(4-fluorobenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

436 Example 2361-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

426 Example 2371-(3,5-dimethylpiperidin-1-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

424 Example 2386-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(1-naphthylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

468 Example 2394-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperazine-1-carbaldehyde

425 Example 2406-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[(6-methylpyridin-2-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

403 Example 2416-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(2-methylbutyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

368 Example 2426-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(pyridin-4-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

388 Example 243(3aR,9bR)-2-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole

454 Example 2441-{4-[2-(4-chlorophenyl)ethyl]piperidin-1-yl}-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

534 Example 2456-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[(1-morpholin-4-ylcyclohexyl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

509 Example 2466-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-(4-methylpiperidin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

410 Example 247N-(2,4-dichlorobenzyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

486 Example 2486-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(3-pyridin-3-ylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

417 Example 2496-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-(4-phenylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

473 Example 250 ethyl1-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperidine-4-carboxylate

468 Example 251N-(2,3-dihydro-1H-inden-5-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 2526-(4-ethoxy-2-methoxyphenyl)-1-[4-(2-fluorophenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

491 Example 2536-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

405 Example 2546-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-[3-[methyl-4-(4-methylphenyl)piperazin-1-yl]-6H-pyrrolo[3,4-d]pyridazine

501 Example 2556-(4-ethoxy-2-methoxyphenyl)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

503 Example 2562-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1,2,3,4-tetrahydroisoquinoline

444 Example 2571-(4-{4-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperazin-1-yl}phenyl)ethanone

515 Example 2586-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(4-methylcyclohexyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

424 Example 259N-(3,3-diphenylpropyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

522 Example 2606-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[2-(1,3-thiazol-2-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

409 Example 2616-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-[2-(3-phenylpyrrolidin-1-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

501 Example 2626-(4-ethoxy-2-methoxyphenyl)-N-isobutyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

384 Example 2631-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

531 Example 2644-(4-chlorophenyl)-1-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperidin-4-ol

522 Example 2656-(4-ethoxy-2-methoxyphenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

491 Example 2661-[4-(4-chlorophenyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

507 Example 2676-(4-ethoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 268N-(1H-benzimidazol-2-ylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

428 Example 2691-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol

556 Example 270 ethyl1-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperidine-3-carboxylate

468 Example 2716-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(pyridin-3-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

388 Example 272N-(3,4-difluorobenzyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

423 Example 2736-(4-ethoxyphenyl)-N-(3-fluorobenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

405 Example 2746-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-[3-methyl-4-(3-methylphenyl)piperazin-1-yl]-6H-pyrrolo[3,4-d]pyridazine

501 Example 2756-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-{4-[(2E)-3-phenylprop-2-en-1-yl]piperazin-1-yl}-6H-pyrrolo[3,4-d]pyridazine

513 Example 2766-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(pyrazolo[1,5-a]pyridin-7-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

428 Example 2776-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(pyrazolo[1,5-a]pyridin-7-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

428 Example 278N-[2-(4-chlorophenyl)ethyl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

436 Example 2791-[4-(3,4-dimethylphenyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

501 Example 2806-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(1-phenylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

402 Example 281N-[2-(2,4-dichlorophenyl)ethyl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

500 Example 282N-(3,4-dimethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

434 Example 2832-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-2,3,4,9-tetrahydro-1H-beta-carboline

453 Example 2848-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-N-(2-pyrrolidin-1-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

425 Example 2856-(4-ethoxyphenyl)-N-isobutyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pylidazin-1-amine

353 Example 2868-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1,4-dioxa-8-azaspiro[4.5]decane

454 Example 2872-({[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}methyl)quinazolin-4(3H)-one

456 Example 2881-[4-(2,4-dimethylphenyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

501 Example 2896-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(2-phenylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

402 Example 2901-(3,3-diphenylpyrrolidin-1-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

504 Example 291N-{1-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]pyrrolidin-3-yl}acetamide

409 Example 2926-(4-ethoxy-2-methoxyphenyl)-1-(4-ethylpiperazin-1-yl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

425 Example 293N-cyclopentyl-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

365 Example 2946-(4-ethoxy-2-methoxyphenyl)-1,5,7-trimethyl-4-piperidin-1-yl-6H-pyrrolo[3,4-d]pyridazine

396 Example 295N-(1-benzothien-2-ylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

444 Example 296N′-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-diethylethane-1,2-diamine

427 Example 2971′-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1,4′-bipiperidine

479 Example 2986-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(3-phenylpropyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

416 Example 2996-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(2-morpholin-4-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

411 Example 300N′-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-diethylethane-1,2-diamine

397 Example 301N-(1,3-dihydro-2-benzofuran-5-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

416 Example 3026-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

428 Example 3036-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[2-(trifluoromethyl)benzyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

455 Example 3046-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

471 Example 3052-(2-{[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]amino}ethyl)quinazolin-4(3H)-one

470 Example 3066-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(4-phenylbutyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

430 Example 3076-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-N-(2-pyridin-2-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

417 Example 3086-(4-ethoxyphenyl)-1,5,7-trimethyl-4-pyrrolidin-1-yl-6H-pyrrolo[3,4-d]pyridazine

351 Example 3091-[6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d[pyridazin-1-yl]-N,N-diethylpiperidine-3-carboxamide

495 Example 310N-(2,3-dimethylcyclohexyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

408 Example 3116-(4-ethoxyphenyl)-N-(2-methoxyethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

355 Example 312N-(2,3-dihydro-1H-inden-5-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

414 Example 313N-(2,4-dichlorobenzyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

456 Example 314N-1,3-benzodioxol-5-yl-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

417 Example 3156-(4-ethoxyphenyl)-N-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

404 Example 3166-(4-ethoxyphenyl)-1,5,7-trimethyl-4-piperidin-1-yl-6H-pyrrolo[3,4-d]pyridazine

365 Example 317N-(1,3-dimethylbutyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

412 Example 3181-[4-(3,4-dichlorophenyl)piperazin-1-yl]-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

541 Example 3196-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[4-(methylthio)phenyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

420 Example 3206-(4-ethoxyphenyl)-N-(3-methoxybenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

418 Example 3211-(4-cyclohexylpiperazin-1-yl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

479 Example 3221-(4-benzylpiperazin-1-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

457 Example 3236-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-phenylazepan-1-yl)-6H-pyrrolo[3,4-d]pyridazine

456 Example 3246-(4-ethoxyphenyl)-N-(isoquinolin-8-ylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

439 Example 325N-(2-ethoxybenzyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

432 Example 326N-(1,3-dimethylbutyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

382 Example 3276-(4-ethoxyphenyl)-N-(3-fluoro-4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

405 Example 328N-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1H-1,2,3-benzotriazol-5-amine

414 Example 3296-(4-ethoxyphenyl)-N-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

404 Example 330N-(3,3-diphenylpropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

492 Example 3316-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-methylpiperidin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

380 Example 3322-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1,2,3,4-tetrahydroisoquinoline

414 Example 333N′-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-dimethylethane-1,2-diamine

368 Example 3346-(4-ethoxyphenyl)-1,5,7-trimethyl-4-[(1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl]-6H-pyrrolo[3,4-d]pyridazine

434 Example 3351′-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-1,4′-bipiperidine

449 Example 3366-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-phenylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

443 Example 3376-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-pyridin-2-ylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

444 Example 3381-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

501 Example 3396-(4-ethoxyphenyl)-N-(4-isopropylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

416 Example 3401-[4-(3,4-dimethylphenyl)piperazin-1-yl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

471 Example 3416-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[3-(2-methylpiperidin-1-yl)propyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

437 Example 342N-(1-benzylpiperidin-4-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

471 Example 343N-(3-chloro-4-morpholin-4-ylphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

493 Example 3446-(4-ethoxyphenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

461 Example 3451-(3,5-dimethylpiperidin-1-yl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

394 Example 3466-(4-ethoxyphenyl)-N-(4-methoxybenzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

418 Example 3476-(4-ethoxyphenyl)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

473 Example 348N′-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-diethylpropane-1,3-diamine

411 Example 3496-(4-ethoxyphenyl)-1-[4-(2-fluorophenyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

461 Example 350N-benzyl-6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

402 Example 3511-{4-[2-(4-chlorophenyl)ethyl]piperidin-1-yl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

504 Example 352N~4~-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N~1~,N~1~-diethylpentane-1,4-diamine

439 Example 3536-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[4-(trifluoromethyl)benzyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

455 Example 3541-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol

526 Example 355N-[3,5-bis(trifluoromethyl)benzyl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

523 Example 3566-(4-ethoxyphenyl)-4,5,7-trimethyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-6H-pyrrolo[3,4-d]pyridazin-1-amine

409 Example 3576-(4-ethoxyphenyl)-1,5,7-trimethyl-4-morpholin-4-yl-6H-pyrrolo[3,4-d]pyridazine

367 Example 3586-(4-ethoxyphenyl)-1-[4-(2-furoyl)piperazin-1-yl]-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

461 Example 3594-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]piperazine-1-carbaldehyde

394 Example 3606-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-methylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

381 Example 3611-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

396 Example 3626-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(pyridin-2-ylmethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

388 Example 3636-(4-ethoxyphenyl)-4,5,7-trimethyl-N-(2-pyrrolidin-1-ylethyl)-6H-pyrrolo[3,4-d]pyridazin-1-amine

395 Example 3641-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N,N-diethylpiperidine-3-carboxamide

465 Example 365N-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-N-ethyl-N′,N′-dimethylethane-1,2-diamine

397 Example 3666-(4-ethoxyphenyl)-1,5,7-trimethyl-4-(4-methylpiperazin-1-yl)-6H-pyrrolo[3,4-d]pyridazine

381 Example 3676-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

327

EXAMPLE 3686-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85,1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineand hydrazine (0.10 mL, 0.32 mmol) reacted to give6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine:¹H NMR (CDCl₃, 500 MHz) δ 7.03-7.11 (m, 4H), 4.12 (q, 2H), 2.43 (s, 3H),2.36 (s, 3H), 2.28 (s, 3H), 1.69 (s, 2H), 1.50 (t, 3H); MS (ESI) 312(M+H)⁺.

EXAMPLE 3696-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

A solution of1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine(EXAMPLE 85) (100 mg, 0.32 mmol) and MeOH (5 mL) was treated with asolution of NaOMe (freshly prepared from MeOH (5 mL) and sodium metal(22 mg, 0.96 mmol)). The resulting mixture was placed in a resealablereaction vessel and heated at 100° C. for 12 h. The reaction was allowedto cool to rt, and poured into ice water (100 mL) to give6-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine:¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.25 (m, 4H), 4.16 (q, 2H), 2.71 (s, 3H),2.40 (s, 3H), 2.38 (s, 3H), 1.43-1.46 (t, 3H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 370 6(4-ethoxyphenyl)-2,4,5,7-tetramethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

A solution ofethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate(prepared as in EXAMPLE 85) (70 mg, 0.20 mmol) and MeOH (5 mL) in aresealable reaction vessel was mixed with methylhydrazine (0.032 mL,0.60 mmol) and AcOH (˜3 drops). The vessel was sealed and heated at 70°C. for 12 h. The resulting slurry was allowed to cool to rt and pouredinto ice water (50 mL). The resulting white solid was filtered and driedunder vacuum for 8 h to give6-(4-ethoxyphenyl)-2,4,5,7-tetramethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one:¹H NMR (CDCl₃, 500 MHz) δ 7.00-7.26 (m, 4H), 4.10 (q, 2H), 3.71 (s, 3H),2.49 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 1.48 (t, 3H); MS (ESI) 312(M+H)⁺.

EXAMPLE 3716-(4-ethoxyphenyl)-5-phenyl-1,4,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 1-phenyl-1,4-pentanedione (1.06g, 6.0 mmol) and toluene(50 mL) was added p-phenetidine (0.78 mL, 6.0 mmol) and 5 drops ofglacial acetic acid. The mixture was heated at reflux overnight. Aftercooling to rt, the mixture was concentrated in vacuo and purified byflash chromatography on silica gel (15-25% EtOAc/hexanes) to give1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole as a yellow solid: ¹H NMR(CDCl₃, 500 MHz) δ 7.17-7.13 (m, 2H), 7.10-7.05 (m, 5H), 6.89-6.84 (m,2H), 6.35 (d, 1H), 6.08 (d, 1H), 4.04 (q, 2H), 2.13 (s, 3H), 1.44 (t,3H); MS (ESI) 278 (M+H)⁺.

Acetyl chloride (0.36 mL, 5.0 mmol) and SnCl₄ (5.0 mL of a 1.0 Msolution in CH₂Cl₂, 5.0 mmol) were added dropwise to a stirring solutionof 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole (554 mg, 2.0 mmol) andtoluene (10 mL) at 0° C. The mixture was warmed to rt and then heated at50° C. overnight. Following cooling to rt, the mixture was diluted with1N NaOH (50 mL), extracted with EtOAc (100 mL), the organic layer washedwith brine, dried (MgSO₄), filtered, concentrated in vacuo, and purifiedby flash chromatography on silica gel (0-30% EtOAc/hexanes). Theresulting diacetylpyrrole was dissolved in EtOH (10 mL) and hydrazine(0.5 mL) and the mixture was heated at 50° C. for 2h. The mixture wascooled to rt and poured into ice water (50 mL). The resulting solid wasfiltered to give6-(4-ethoxyphenyl)-5-phenyl-1,4,7-trimethyl-6H-pyrrolo[3,4-d]pyridazineas a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.26-7.23 (m, 3H), 7.16-7.13(m, 2H), 7.00-6.97 (m, 2H), 6.84-6.81 (m, 2H), 3.99 (q, 2H), 2.87 (s,3H), 2.53 (s, 3H), 2.27 (s, 3H), 1.40 (t, 3H); MS (M+H)⁺ 358.58.

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

1. A method of binding the α₂δ subunit of voltage gated calcium channelscomprising a step of administering to a patient in need thereof aneffective amount of a compound represented by Formula (I) selected from:

or a pharmaceutically acceptable salt thereof.
 2. A compound selectedfrom:

or a pharmaceutically acceptable salt thereof.
 3. A compound representedby Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is—C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl,—C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸,—N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸,—SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or—C(═NOR⁶)R⁷ substituents; R^(2,) and R^(3,) each independently is—C₁₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl,—C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C⁰⁻⁶alkyl-heteroC₃₋₇cycloalkyl,optionally substituted with 1-6 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷,—NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷,—COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents; R⁴,and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl,—C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen,—CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸,—NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸,—SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷substituents; and R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl,—C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) substituents, wherein when the carbon atom in—C₀₋₆alkyl equals “0” then no alkyl is present; provided that thecompound is not 6-methyl-6H-pyrrolo[3,4-d]pyridazine,1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine,5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine,N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide,1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate,1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine,5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,5,7-dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide,2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafloroborate 5,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,6-benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo[3,4-d]pyridazine,6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine,6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine,9,12-diphenyl-pyridazino[4′, 5′:3,4]pyrrolo[2, 1-a]isoquinoline,5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethylester, 7,10-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline,11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine,1-oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2.1-c]benzoxazine-1,4,10-methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine,11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine,1,4-dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,1-chloro-4-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride,1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate,1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridaziniumtetrafluoroborate, 1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,5-cyano-1,4-dimethylpyridazino[4,5-a]indolizine,1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine,6-methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,5,7-dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile,dimethyl3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate,5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol,5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride,3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4d]pyridine, or1,4-diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole; and is notselected from the following table: